molecules

Review Structure-Activity Relationship of Derived Compounds for the Treatment of Neuronal Activity-Related Diseases

Cristina Prandi 1, Marco Blangetti 1, Dvora Namdar 2 and Hinanit Koltai 2,* 1 Department of Chemistry, University of Turin, 10125 Torino, Italy; [email protected] (C.P.); [email protected] (M.B.) 2 ARO, Volcani Center, Rishon LeZion 7505101, Israel; [email protected] * Correspondence: [email protected]; Tel.: +972-3-968-3039

Academic Editor: Antonio Evidente  Received: 22 May 2018; Accepted: 23 June 2018; Published: 25 June 2018 

Abstract: Cannabis sativa active compounds are extensively studied for their therapeutic effects, beyond the well-known psychotropic activity. C. Sativa is used to treat different medical indications, such as multiple sclerosis, spasticity, epilepsy, ulcerative colitis and pain. Simultaneously, basic research is discovering new constituents of cannabis-derived compounds and their receptors capable of neuroprotection and neuronal activity modulation. The function of the various phytochemicals in different therapeutic processes is not fully understood, but their significant role is starting to emerge and be appreciated. In this review, we will consider the structure-activity relationship (SAR) of compounds able to bind to cannabinoid receptors and act as therapeutic agents in neuronal diseases, e.g., Parkinson’s disease.

Keywords: Cannabis sativa; structure-activity relationship; phytocannabinoids; endocannabinoids; cannabinoid receptors; neuronal diseases; Parkinson’s disease

1. Introduction The marijuana plant, Cannabis sativa L., produces hundreds of secondary metabolites. C. sativa produces a diverse group of isoprenylated resorcinyl polyketides commonly named phytocannabinoids. The ‘Lego-like’ building pathways of phytocannabinoids, via the non-enzymatic transformations induced by heat, light, and atmospheric oxygen, result in different resorcinyl side-chain, or variation in oligomerization degree of the isoprenyl end, creating alkyl- and a β-aralklyl chemotypes [1]. These include around 110 characteristic phytocannabinoids [2,3], the most studied of which are (∆9-, THC) and (CBD). This plant has been known for thousands of years for its effect on the human body [2,3]. The psychoactive effect of C. sativa, produced by only one of its hundreds of constituents [4,5] presumably led to its cultivation more than 6000 years ago [6–8]. Ancient C. sativa is believed to be used for various social and ritualistic purposes, and even in palliative and medicinal applications [9–11]. Today, C. sativa is used medicinally to treat various medical indications. The integrated inventory of these compounds and their biological macromolecular end-points highlight the opportunities that phytocannabinoids offer to access desirable drug-like effects, beyond the one associated with the narcotic target CB1 [1]. The main active compound with psychotropic effects produced by the plant THCA, heated into the decarboxylate active THC [4], is probably the compound that alleviates chronic neuropathic pain [12–14], nausea, headaches, and fatigue. However, other active compounds of C. sativa may account for their additional medical activities in various tissues and body parts, such as epilepsy [15], chemotherapy-induced nausea [16], anorexia [17], multiple sclerosis

Molecules 2018, 23, 1526; doi:10.3390/molecules23071526 www.mdpi.com/journal/molecules Molecules 2018, 23, 1526 2 of 17 spasticity [18–21], fibromyalgia and rheumatoid arthritis [12–14], glaucoma intraocular pressures [22], and asthma-associated dyspnea [23]. Besides phytocannabinoids, C. sativa produces more than 400 other phytochemicals including terpenoids and terpenes, flavonoids, and hydrocarbons [24]. Although a complete and unified inventory of phytocannabinoids has recently been published [1], there remains much to learn about the activity of the different phytochemicals, their modes of action on human body and their structure-activity relationships (SAR). In this review, we will focus on the SAR of natural and synthetic compounds of C. sativa that may bind G-protein-coupled cannabinoid receptors and may be beneficial in the treatment of neuronal diseases, e.g., Parkinson’s disease.

1.1. Receptors and Endocannabinoids Three types of G-protein-coupled cannabinoid receptors (GPCR) are known to-date—first, CB1, cloned in 1990 and CB2, cloned in 1993 [25,26] were widely recognized and studied as cannabinoids effective targets [27]. Much later, a third G-protein-coupled cannabinoid, receptor 55, was suggested as CB3 [28,29]. The CB3 shares several cannabinoid ligands with the two previously recognized GPCRs, but with only low homology to the classical cannabinoid receptors [30]. Its pathophysiology is still vague and its functions in the central nervous system are not yet understood, although CB3 was shown to be expressed in several brain areas [31]. Evidence also suggested that cannabinoids bind to and act via nuclear, peroxisome proliferator-activated receptors (PPARs, with three subtypes α, β (δ) and γ)[32]. Cannabinoid receptors are distributed in the human body, mainly in the central nervous system, but also in other peripheral tissues including the spleen, the reproductive, urinary and gastrointestinal tracts, the endocrine glands, the arteries and the heart [33]. The existence of additional subtypes in the was investigated [34–37]. Modulation of the endocannabinoid system using C. sativa has promising therapeutic effects in the treatment of various disorders, such as neurodegenerative diseases [38], epilepsy [39], cognitive deficits [40], and others. However, producing cannabinoid-derived drugs to treat these disorders by regeneration or modification of the endocannabinoid system is highly challenging and has yet to be achieved [41,42]. Endocannabinoids are produced in the body when needed, under stress, or in response to synaptic activity [43]. The most studied endocannabinoids are the orthosteric (AEA) and 2-AG [44,45]. They are considered to be dominant and are agonists for CB1 and CB2 receptors, with higher affinity to CB1 binding [46]. Further pharmacological characterization is still needed to thoroughly understand the physiological roles of endocannabinoids and their modes of action [42]. Nevertheless, pharmacological manipulation of endocannabinoid levels may provide new opportunities to regulate the endocannabinoid system and treat the related disorders [47].

1.2. Phytocannabinoids Originally, the term “cannabinoid” referred to a homogeneous class of monoterpenoids typical of C. sativa L. More recently, the term “cannabinoids” has been extended to all those compounds showing an affinity for the GPCR known as cannabinoid receptors, CB1 and CB2, independently from their monoterpenoid skeleton (very little is known about GPR55, also named CB3, in this respect). The endogenously produced analogues showing affinity for CB1 and CB2 are known as endocannabinoids. To differentiate from this latter class of compounds, the term phytocannabinoids has been introduced to emphasize the botanical origin of these cannabinoids. Among the known plant-derived cannabinoids, the most abundant are (THCs), cannabidiols (CBDs), and (CBNs), followed by cannabigerols (CBGs), cannabichromenes (CBCs) and cannabinodiols (CBNDs, Figure1)[48]. Classical phytocannabinoids are tricyclic terpenoid compounds bearing a benzopyran moiety soluble in lipids and non-polar organic solvents. The phenolic compounds are soluble as phenolate salts form under basic conditions. In the plant, the carboxylated form of the cannabinoids is more Molecules 2018, 23, 1526 3 of 17 abundant, named “acid” and indicated as THCA, CBDA, CBGA and similar. The psychoactive compounds are the decarboxylated form of the varieties, i.e., THC, etc. There are some variations in the length of the C-3 side chain, pentyl being the most common but n-propyl derivatives are also well known. The n-propylated analogues with their shorter chain are named using the suffix “varin” and indicated as THCV, CBDV and similar [49]. As mentioned above, phytocannabinoids are classified, based on the resorcinol side-chain, into two main classes: (a) alkyl and (b) β-aralkyl (Table1). As the β-aralkyl side chain derives from an aromatic starter, its residue replaces the alkyl group of the parent compounds. Subclasses of these two main classes are further identified based on the nature of the side-chain and on the presence of O-bridges with a resorcinol core [1].

1.2.1. (CBG) Compounds Compounds belonging to this class do not show psychotrophic activity and are characterized by the presence of a linear non-oxygenated isoprenyl residue. Apart from the decarboxylated compounds CBG and CBGV (Figure1) and their carboxylic parent forms (R 2 = COOH, CBGA), all other CBGA related compounds are minor constituents in cannabis production. They show low affinity for CB1, even though prenylogation increases affinity for CB2. In addition, a quinone derivative of CBG possibly binds at the PPARγ receptor [50]. Indeed, as typical of CBG belonging to the β-aralkyl class, amorfructin B (5, Figure1)[51,52] has been demonstrated to be a powerful ligand of PPAR γ [53]. From the basic formula of CBG, the plant further converts and produces other cannabinoids, mainly CBC, CBD or THC, depending on the enzymes active in the process. Degradation of these compounds occurs spontaneously in the plant and results in CBN, among others. Here, we explore the biosynthesis pathway of these major cannabinoids.

1.2.2. (CBC) Compounds In this type of phytocannabinoid, the isoprenyl side chain is oxidatively fused to the resorcinol ring. The occurrence of CBC in many strains of C. sativa is often associated with ∆9-THC, suggesting a common biosynthetic path from the common precursor CBG. Natural CBC is racemic, shows a blue fluorescence under UV light, and does not exhibit any affinity for CB1 receptors [54].

1.2.3. Cannabidiol (CBD) Compounds The non-narcotic CBD is the major phytocannabinoid component in fiber hemp. The oxidase involved in the formation of the non-narcotic CBD from CBG are not related to those involved in the formation of CBC and THC. The independence of the biosynthetic pathways leading to CBD and to ∆8-THC and ∆9-THC, as well as the observation that the two compounds are not interconverted in cannabis tissues [55] increases the possibility of separating the narcotic effects from the therapeutic ones. The elucidation of the absolute configuration was made based on the correlation with natural (-) . For the compounds of the same class of the β-aralkyl series, only a few compounds have been isolated with absolute and/or relative configurations different from those isolated from cannabis. Machaeridiol A, B, C (8, Figure1), used as antimalaric agents, are representatives of this class [56]. Molecules 2018, 23, 1526 4 of 17 Molecules 2018, 23, x FOR PEER REVIEW 4 of 16

MoleculesMolecules 20182018,, 2323,, xx FORFOR PEERPEER REVIEWREVIEW 44 ofof 1616

Figure 1. Structure of narcotic phytocannabinoids Δ8-THC, Δ9-THC, CBN with high affinity for Figure 1. 8 9 ligandsStructure CB1 and of CB2 narcotic and of phytocannabinoids non-narcotic phytocannabinoids∆ -THC, ∆ -THC,CBG and CBN CBD. with Numbering high affinity system for and ligands CB1FigureFigure andbinding CB21.1. StructureStructure affinities and of non-narcotic ofofare narcoticnarcot reported.ic phytocannabinoidsphytocannabinoids phytocannabinoids ΔΔ88--THC,THC, CBG andΔΔ99--THC,THC, CBD. CBNCBN Numbering withwith highhigh system affinityaffinity and forfor binding affinitiesligandsligands areCB1CB1reported. andand CB2CB2 andand ofof nonnon-narcotic-narcotic phytocannabinoidsphytocannabinoids CBGCBG andand CBD.CBD. NumberingNumbering systemsystem andand bindingbinding affinitiesTableaffinities 1. Phytocannabinoids areare reported.reported. classification based on the nature of the resorcinyl side-chain.1 Table 1. Phytocannabinoids classification based on the nature of the resorcinyl side-chain.1 TableTable 1.1. PhytocannabinoidsPhytocannabinoids cclassificationlassification basedbased ononAlkyl thethe naturenature ofof thethe resorcinylresorcinylβAralkyl sideside-chain.-chain .11

AlkylAlkylAlkyl βAralkylβAralkylβAralkyl Cannabigerol (CBG) OH R3

R Cannabigerol (CBG) 1 R O MoleculesMolecules 2018 2018, 23, 23, x,Cannabigerol Cannabigerol FORx FOR PEER PEER REVIEW REVIEW (CBG)(CBG) 2 5 of5 of 16 16 R4

R R4 4 OHOH OH OH COOHCOOH R1 R1 Cannabichromene (CBC) O O CannabichromeneCannabichromene (CBC) (CBC) O O R2 R2 R3 R3 R3 R3

CannabidiolCannabidiol (CBD) (CBD)

TetrahydrocannabinolTetrahydrocannabinol (THC) (THC)

CannabinolCannabinol (CBN) (CBN) - -

1 Only1 Only principal principal classes classes are are reported reported and and selected selected for for the the focus focus of of this this review. review. For For a completea complete inventory, inventory, see see [1]. [1].

1.2.4.1.2.4. Tetrahydrocannabinol Tetrahydrocannabinol (THC) (THC) Compounds Compounds

TheThe most most abundant abundant and and best-known best-known component component of of this this class class is is Δ 9Δ-THC,9-THC, alongside alongside a aplethora plethora of of minorminor constituents constituents that that may may result result from from degradation degradation or or modifications modifications of of Δ 9Δ-THC9-THC itself. itself. In In Δ 8Δ-THC,8-THC, thethe double double bond bond remains remains in in a athermodynamically thermodynamically more more stable stable position, position, and, and, as as a aresult, result, a ashift shift of of the the doubledouble bond bond from from nine nine to to eight eight positions positions is is the the preferred preferred process process [1]. [1]. The The comprehensive comprehensive stereochemistrystereochemistry of of the the structure structure of of Δ 9Δ-THC9-THC was was completely completely elucidated elucidated in in 1964 1964 [1]. [1]. Δ 9Δ-THC9-THC is is less less stablestable than than its its isomer isomer Δ 8Δ-THC8-THC and and easily easily undergoes undergoes isomerization isomerization of of the the double double bond bond or or to to abstraction abstraction ofof the the H H in in position position 10a 10a (both (both benzylic benzylic and and allylic) allylic) and and elimination elimination to to a aconjugate conjugate diene, diene, possibly possibly a a precursorprecursor of of the the aromatic aromatic CBN. CBN. The The native native form form of of Δ 9Δ-THC9-THC is is represented represented by by a amixture mixture of of two two carboxylatedcarboxylated pre-cannabinoids, pre-cannabinoids, Δ 9Δ-THCA9-THCA and and Δ 9Δ-THCB.9-THCB. The The carboxylic carboxylic derivative derivative Δ 9Δ-THCA9-THCA shows shows potentpotent neuroprotectiveneuroprotective activity,activity, whichwhich isis worthworth consideringconsidering forfor neurodegenerativeneurodegenerative andand neuroinflammatoryneuroinflammatory diseases diseases [57]. [57]. Δ 9Δ-THC9-THC acts acts as as a apartial partial agonist agonist of of CB1 CB1 and and CB2 CB2 [58]. [58].

1.2.5.1.2.5. Cannabitriol Cannabitriol (CBT) (CBT) and and Cannabelsoin Cannabelsoin (CBE) (CBE) Compounds Compounds TheseThese are are minor minor constituents constituents of of cannabis cannabis extracts, extracts, occurring occurring in in only only part part of of C. C. sativa sativa sub-species. sub-species. CBTCBT (10 (10, Figure, Figure 1) 1) was was the the first first to to be be recognized recognized and and isolated isolated [59] [59] and and only only a adecade decade later later its its chemical chemical structurestructure was was recognized recognized [60]. [60]. CBE CBE (11 (11, Figure, Figure 1) 1) is is produced produced by by the the plant plant in in negligible negligible amounts amounts but but isis also also a amammalian mammalian metabolite metabolite of of CBD CBD [61]. [61].

1.2.6.1.2.6. Cannabinoids Cannabinoids Degradant: Degradant: Cannabinol (CBN) (CBN) and and Cannabicyclol (CBL) (CBL) Compounds Compounds CannabinolCannabinol was was the the first first phytocannabinoid phytocannabinoid structurally structurally characterized. characterized. Cannabinol Cannabinol and and its its derivativesderivatives are are now now considered considered to to be be the the oxidative oxidative by-product by-product of of the the degradation degradation process process of of THC THC andand CBD CBD compounds. compounds. CBC CBC is is photo-degraded photo-degraded into into CBL. CBL. The The cannabinoid cannabinoid degradants degradants CBN CBN and and CBL CBL (12(12, Figure, Figure 1) 1) show show low low affinity affinity for for both both CB1 CB1 and and CB2. CB2.

1.2.7.1.2.7. Miscellaneous Miscellaneous Cannabinoids Cannabinoids ThereThere are are other other cannabinoids cannabinoids not not categorized categorized in in a aclass: class: 10-oxo- 10-oxo-Δ-6a-tetrahydrocannabinolΔ-6a-tetrahydrocannabinol (OTHC);(OTHC); Cannabichromanon Cannabichromanon (CBC (CBCF);F); Cannabifuran Cannabifuran (CBF) (CBF) and and dehydrocannabi dehydrocannabifuranfuran (DCBF); (DCBF); Cannabiglendol;Cannabiglendol; Cannabiripsol Cannabiripsol (CBR); (CBR); Cannabicitran Cannabicitran (CBT); (CBT); Δ 9Δ-cis-tetrahydrocannabinol9-cis-tetrahydrocannabinol (cis-THC); (cis-THC); andand Tryhydroxy- Tryhydroxy-Δ9Δ-tetrahydrocannabinol9-tetrahydrocannabinol (triOH-THC) (triOH-THC) [62]. [62]. However, However, their their relative relative amounts amounts in in the the plantplant are are low. low.

Molecules 2018, 23, x FOR PEER REVIEW 5 of 16 MoleculesMoleculesMolecules2018 2018 2018, 23, ,23 23,, 1526 ,x x FOR FOR PEER PEER REVIEW REVIEW 55 of of 16 16 5 of 17 MoleculesMolecules 2018 2018, 23, ,23 x ,FOR x FOR PEER PEER REVIEW REVIEW 5 of5 16of 16 R 4 OH OH R4 R4 OHCOOH OH OHR1 OH Cannabichromene (CBC) COOHCOOH R R1 Table 1. Cont. 1 O CannabichromeneCannabichromene (CBC) (CBC) O R2 R O O R3 CannabichromeneCannabichromene (CBC) (CBC) O O 3 R2 R2 R R3 R R3 3 Alkyl 3 β Aralkyl

Cannabidiol (CBD) CannabidiolCannabidiolCannabidiol (CBD) (CBD) (CBD) Cannabidiol (CBD) Cannabidiol (CBD)

TetrahydroTetrahydrocannabinolcannabinol (THC) (THC) TetrahydrocannabinolTetrahydrocannabinol (THC) (THC) TetrahydrocannabinolTetrahydrocannabinol (THC) (THC)

Cannabinol (CBN) - Cannabinol (CBN) - CannabinolCannabinol (CBN) (CBN) -- CannabinolCannabinol (CBN) (CBN) - - 1 Only principal classes are reported and selected for the focus of this review. For a complete inventory, see [1]. 1 Only principal classes are reported and selected for the focus of this review. For a complete inventory, see [1]. 1 1Only Only principal principal classes classes are are reported reported and and selected selected for for the the focus focus of of this this review. review. For For a a complete complete inventory, inventory ,see see [1]. [1] . 1 Only1 Only principal principal classes classes are are reported reported and and selected selected for for the the focus focus of ofthis this review. review. For For a complete a complete inventory, inventory, see see [1]. [1]. 1.2.4.1.2.4 Tetrahydrocannabinol. Tetrahydrocannabinol (THC) (THC) C Compoundsompounds 1.2.4. Tetrahydrocannabinol (THC) Compounds 1.2.4. Tetrahydrocannabinol (THC) Compounds 9 1.2.4.1.2.4.The TheTetrahydrocannabinol Tetrahydrocannabinol most most abundant abundant and (THC) best best-known(THC)-known Compounds Compounds component component of this of thisclass class is Δ9- isTHC,∆ -THC, alongside alongside a plethora a plethora of of 99 TheThe most most abundant abundant and and best-known best-known component component of of this this class class is is Δ Δ-THC,-THC,9 alongside alongside9 a a plethora plethora8 of of 8 minorminorThe constituents Theconstituents most most abundant abundant thatthat mayand and best-knownresult result best-known from from componentdegradation degradationcomponent of or ofthis modifications orthis class modifications class is Δis9 -THC,Δ 9of-THC, Δ alongside- ofTHC alongside∆ -THCitself. a plethoraaIn itself. plethora Δ -THC In of ∆ ,of -THC, minorminor constituentsconstituents thatthat maymay resultresult from from degradationdegradation oror modificationsmodifications ofof ΔΔ9-THC9-THC itself.itself. InIn ΔΔ88-THC,-THC , theminortheminor double double constituents constituents bondbond remains remains that that may inmay in aresult thermodynamically result a thermodynamically from from degradation degradation more or orstablemodifications more modifications position, stable position,ofand ofΔ 9,-THCΔ as9-THC a result, and,itself. itself. a asIn shift InΔ a 8Δ-THC, result, of8-THC, the a shift thethe double double bond bond remains remains in in a a thermodynamically thermodynamically more more stable stable position, position, and, and ,as as a a result, result, a a shift shift of of the the ofdouble thethe double bond bond bond from remains fromnine ninetoin aeight thermodynamically to eightpositions positions is the more is preferred the stable preferred position, process process and, [1] .as The a [ 1result,]. comprehensive The a shift comprehensive of the thedoubledouble double bond bond bond from from remains ninenine in toato thermodynamically eighteight positionspositions isis more thethe preferredstablepreferred position, processprocess and, [1]. [1]as .a The Theresult, comprehensivecomprehensive a shift of the stereochemistry of the structure of Δ9-THC9 was completely elucidated in 1964 [1]. Δ9-THC is less9 stereochemistrydoubledouble bond bond from offrom thenine nine structure to toeight eight ofpositions 99positions∆ -THC is is wasthe the preferred completely preferred process process elucidated [1]. [1]. The The in comprehensive 1964 comprehensive99 [1]. ∆ -THC is stereochemistrystereochemistry ofof thethe 8 structurestructure ofof ΔΔ-THC-THC waswas completelycompletely elucidatedelucidated inin 19641964 [1].[1] . ΔΔ-THC-THC isis lessless stable than its isomer Δ -THC and8 easily9 9 undergoes isomerization of the double bond or9 to9 abstraction lessstereochemistrystereochemistry stable than itsof ofthe isomer the 8structure8 structure∆ -THC of ofΔ Δ-THC and-THC easilywas was completely undergoescompletely elucidated elucidated isomerization in in1964 1964 of[1]. [1]. the Δ -THCΔ double-THC is isless bond less or to stableofstable the than Hthan in its itsposition isomer isomer 10aΔ Δ-THC- (bothTHC and andbenzylic easily easily andundergoes undergoes allylic) isomerization isomerizationand elimination of of the theto doublea double conjugate bond bond diene, or or to to abstraction abstractionpossibly a abstractionstablestable than than its of its isomer the isomer H Δ8 inΔ-THC8-THC position and and easily easily 10a undergoes(both undergoes benzylic isomerization isomerization and allylic)of ofthe the double double and bond elimination bond or orto toabstraction abstraction to a conjugate ofprecursorof thethe HH inin of positionposition the aromatic 10a10a (both(both CBN. benzylicbenzylic The native andand allylic)allylic) form andofand Δ elimination9elimination-THC is represented toto aa conjugateconjugate by a diene, diene, mixture possiblypossibly of two aa of ofthe the H Hin inposition position 10a 10a (both (both benzylic benzylic and and allylic) allylic) and and elimination99 elimination to toa conjugatea conjugate9 diene, diene, possibly possibly a a diene,precursorprecursor possibly of of the the a aromatic precursor aromatic CBN. CBN. of the The9 The aromatic native native form form CBN.9 of of Δ The Δ-THC-THC native isis represented represented form of ∆ by by-THC a a mixture mixture9 is represented of of two two by a precursorcarboxylatedprecursor of ofthe pre the -aromaticcannabinoids aromatic CBN. CBN., ΔThe -THCAThe native native and form Δform-THCB. of ofΔ 9Δ-THC The9-THC carboxylicis isrepresented represented derivative by by a Δmixturea -mixtureTHCA of shows oftwo two mixturecarboxylatedcarboxylated of two pre-cannabinoids, pre carboxylated-cannabinoids pre-cannabinoids, ,Δ Δ99-THCA-THCA and and Δ Δ99-THCB.-THCB.∆9-THCA The The carboxylic carboxylic and ∆9-THCB. derivative derivative The ΔΔ9 carboxylic9-THCA-THCA shows shows derivative potent neuroprotective activity,9 9 which is 9 worth9 considering for neurodegenerative9 9 and 9carboxylatedcarboxylated pre-cannabinoids, pre-cannabinoids, Δ Δ-THCA-THCA and and Δ Δ-THCB.-THCB. The The carboxylic carboxylic derivative derivative Δ Δ-THCA-THCA shows shows ∆ potent-THCApotent neuroprotective neuroprotective shows potent neuroprotectiveactivity, activity, 9which which activity,is is worth worth which considering considering is worth consideringfor for neurodegenerative neurodegenerative for neurodegenerative and and potentneuroinflammatorypotent neuroprotective neuroprotective diseases activity, activity, [57]. Δ which -THCwhich actis s isasworth aworth partial considering consideringagonist of CB1for for andneurodegenerative neurodegenerative CB2 [58]. and and neuroinflammatoryneuroinflammatory diseases diseases [57]. [57] .Δ Δ9-THC9-THC 9acts acts as as a a partial partial agonist agonist of of CB1 CB1 and and CB2 CB2 [58]. [58] . andneuroinflammatoryneuroinflammatory neuroinflammatory diseases diseases diseases [57]. [57]. Δ [9 57-THCΔ9-THC]. ∆ acts-THC acts as asa acts partiala partial as aagonist partialagonist of agonistofCB1 CB1 and and of CB2 CB1CB2 [58]. [58]. and CB2 [58]. 1.2.5. Cannabitriol (CBT) and Cannabelsoin (CBE) Compounds 1.2.5.1.2.5.1.2.5 Cannabitriol .Cannabitriol Cannabitriol (CBT)(CBT) and and Cannabelsoin Cannabelsoin Cannabelsoin (CBE) (CBE) (CBE) Compounds Compounds Compounds 1.2.5.1.2.5. TheseCannabitriol Cannabitriol are minor (CBT) (CBT) constituents and and Cannabelsoin Cannabelsoin of cannabis (CBE) (CBE)extracts, Compounds Compounds occurring in only part of C. sativa sub-species. TheseThese are are minor minor constituents constituents of of cannabis cannabis extracts, extracts, occurring occurring in in only only part part of of C. C. sativa sativa sub-species. sub-species. CBTThese (10,These Figure are are minor 1)minor was constituents theconstituents first to be of recognized cannabis extracts,and extracts, isolated occurring occurring [59] and in onlyonly in only parta decad partof C.e oflatersativaC. its sativasub-species. chemicalsub-species. CBTCBTThese ( (1010,, Figure Figure are minor 1) 1) was was constituents the the first first to to beof be cannabisrecognized recognized extracts, and and isolated isolated occurring [59] [59] inand and only only only part a a decade decadof C. sativae later later sub-species. its its chemical chemical structureCBT (10 ,was Figure recognized 1) was the [60] first. CBE to be (11, recognized Figure 1) isand produced isolated by[59] the and plant only in a negligibledecade later amounts its chemical but CBTCBTstructurestructure ( 10(10,, Figure Figure was was recognized recognized1 1)) waswas the [60]. first[60] first .toCBE CBE to be be ( recognized(1111, recognized, Figure Figure 1) and1) is is and produced isolatedproduced isolated [59] by by [andthe the59 ]plant onlyplant and a in only indecade negligible negligible a decade later amounts itsamounts laterchemical its but but chemical structureisstructure also a mammalianwas was recognized recognized metabolit [60]. [60]. CBEe ofCBE CBD(11 (11, Figure [61], Figure. 1) 1)is producedis produced by by the the plant plant in innegligible negligible amounts amounts but but structureisis also also a a wasmammalian mammalian recognized metabolite metabolit [60]. CBEe of of CBD CBD (11 ,[61]. [61] Figure . 1) is produced by the plant in negligible amounts but is is alsois also a mammaliana mammalian metabolite metabolite of ofCBD CBD [61]. [61]. also1.2.6 a mammalian. Cannabinoids metabolite Degradant: of Cannabinol CBD [61]. (CBN) and Cannabicyclol (CBL) Compounds 1.2.6.1.2.6 .Cannabinoids Cannabinoids Degradant: Degradant: Cannabinol Cannabinol (CBN) (CBN) and and Cannabicyclol Cannabicyclol (CBL) (CBL) Compounds Compounds 1.2.6.1.2.6.1.2.6. Cannabinoids CannabinolCannabinoids Cannabinoids was Degradant: Degradant: Degradant: the first Cannabinol phytocannabinoid CannabinolCannabinol (CBN) (CBN) (CBN) and structurally and andCannabicyclol Cannabicyclol Cannabicyclol characterized. (CBL) (CBL) (CBL)Compounds Compounds Cannabinol Compounds and its CannabinolCannabinol was was the the first first phytocannabinoid phytocannabinoid structurally structurally characterized. characterized. Cannabinol Cannabinol and and its its derivativesCannabinolCannabinol are nowwas was consideredthe the first first phytocannabinoid tophytocannabinoid be the oxidative structurally bystructurally-product characterized.of characterized. the degradation Cannabinol Cannabinol process andof and THC its its derivativesderivativesCannabinol areare nownow was consideredconsidered the first to phytocannabinoidto bebe thethe oxidativeoxidative by-productby structurally-product ofof thethe characterized. degradationdegradation processprocess Cannabinol ofof THCTHC and its derivativesandderivatives CBD compounds. are are now now considered consideredCBC is photo to tobe- degradedbe the the oxidative oxidative into CBL.by-product by-product The cannabinoid of ofthe the degradation degradation degradants process processCBN andof ofTHC CBL THC derivativesandand CBD CBD compounds. compounds. are now considered CBC CBC is is photo-degraded photo to- bedegraded the oxidative into into CBL. CBL. by-productThe The cannabinoid cannabinoid of the degradants degr degradationadants CBN CBN processandand CBL CBL of THC and(12,and CBDFigure CBD compounds. compounds.1) show low CBC affinityCBC is photo-degradedis photo-degradedfor both CB1 and into into CB2. CBL. CBL. The The cannabinoid cannabinoid degradants degradants CBN CBN and and CBL CBL ((1212,, Figure Figure 1) 1) show show low low affinity affinity for for both both CB1 CB1 and and CB2. CB2. and(12(12, CBD Figure, Figure compounds. 1) 1)show show low low CBCaffinity affinity is photo-degradedfor for both both CB1 CB1 and and CB2. into CB2. CBL. The cannabinoid degradants CBN and CBL (121,.2. Figure7. Miscellaneous1) show low Cannabinoids affinity for both CB1 and CB2. 1.2.7.1.2.7 .Miscellaneous Miscellaneous Cannabinoids Cannabinoids 1.2.7.1.2.7. ThereMiscellaneous Miscellaneous are other Cannabinoids Cannabinoids cannabinoids not categorized in a class: 10-oxo-Δ-6a-tetrahydrocannabinol 1.2.7. MiscellaneousThereThere are are other other Cannabinoids cannabinoids cannabinoids not not categorizedcategorized inin a a class: class: 10-oxo- 10-oxo-ΔΔ-6a-tetrahydrocannabinol-6a-tetrahydrocannabinol (OTHC);ThereThere Cannabichromanonare are other other cannabinoids cannabinoids (CBCF); not not categorized Cannabifuran categorized in in (CBF)a aclass: class: and 10-oxo- 10-oxo- dehydrocannabifuranΔ-6a-tetrahydrocannabinolΔ-6a-tetrahydrocannabinol (DCBF); (OTHC);Cannabiglendol;(OTHC); Cannabichromanon Cannabichromanon Cannabiripsol (CBC (CBCF);(CBR);F); Cannabicitran Cannabifuran Cannabifuran (CBT); (CBF) (CBF) Δ 9and- andcis- tetrahydrocannabinol dehydrocannabi dehydrocannabifuranfuran (cis (DCBF); (DCBF);-THC); (OTHC);(OTHC);There Cannabichromanon areCannabichromanon other cannabinoids (CBC (CBCF); notF); Cannabifuran Cannabifuran categorized (CBF) in(CBF) a class:9and9 and dehydrocannabi 10-oxo-dehydrocannabi∆-6a-tetrahydrocannabinolfuranfuran (DCBF); (DCBF); Cannabiglendol;Cannabiglendol; Cannabiripsol Cannabiripsol9 (CBR); (CBR); Cannabicitran Cannabicitran (CBT);(CBT); ΔΔ-cis-tetrahydrocannabinol-cis-tetrahydrocannabinol (cis-THC); (cis-THC); Cannabiglendol;andCannabiglendol; Tryhydroxy -CannabiripsolΔ Cannabiripsol-tetrahydrocannabinol (CBR); (CBR); Cannabicitran Cannabicitran (triOH-THC) (CBT); (CBT); [62] .Δ Howe9 -cis-tetrahydrocannabinolΔ9-cis-tetrahydrocannabinolver, their relative amounts (cis-THC); (cis-THC); in the (OTHC);andand Tryhydroxy- Tryhydroxy Cannabichromanon-ΔΔ99-tetrahydrocannabinol-tetrahydrocannabinol (CBCF); (triOH-THC) (triOH Cannabifuran-THC) [62]. [62] (CBF) .However, However, and their their dehydrocannabifuran relative relative amounts amounts in in the the (DCBF); andplantand Tryhydroxy- areTryhydroxy- low. Δ9Δ-tetrahydrocannabinol9-tetrahydrocannabinol (triOH-THC) (triOH-THC) [62]. [62]. However, However,9 their their relative relative amounts amounts in inthe the Cannabiglendol;plantplant are are low. low. Cannabiripsol (CBR); Cannabicitran (CBT); ∆ -cis-tetrahydrocannabinol (cis-THC); andplantplant Tryhydroxy- are are low. low. ∆9-tetrahydrocannabinol (triOH-THC) [62]. However, their relative amounts in the plant are low.

Molecules 2018, 23, 1526 6 of 17

2. Discussion

2.1. Structure-Activity Relationship (SAR) of Cannabis-Derived Compounds for the Cannabinoid Receptors The main goal in the study of the structure-activity relationship (SAR) of cannabis-derived compounds for the cannabinoid receptors is understanding the receptor binding sites. Currently, only the crystal structure of the human cannabinoid receptor CB1 has been fully achieved [63]. Deciphering the SAR of phytocannabinoids may help further understand the pharmacology and medicinal chemistry of the cannabinoid receptors in order to develop targeted remedies [64]. Moreover, understanding the SAR mechanisms of cannabinoids with their receptors may help the clinical research find new substances with therapeutic effects [65] and with minimized side-effects on cognitive functions. Over the past 60 years, considerable research in medicinal chemistry has been carried out towards the SAR development of the natural classical cannabinoids; only in 1986 did the research group of R. K. Razdan analyze the SAR of about 300 cannabinoid analogues based on their activity in different animal models [66]. After the identification of ∆9-THC in 1964 [67], several chemical modifications of the side chain and/or the tricyclic scaffold led to the characterization of families of potent selective ligands that could be involved in the activation of the main cannabinoid receptor. It has been shown that the n-pentyl chain at the C-(3) position (Figure1), incorporated during the biosynthesis of olivetolic acid [49], represents the key pharmacophoric group of THC [68,69] and modification in this side chain leads to critical changes in the affinity, selectivity and pharmaco-potency of these ligands relating to the cannabinoid receptors (Figure2). In general, a shorter chained alkyl group reduces the potency of the compound to interact with the receptor. In THC, for example, a propyl group at C-(3) creates THCV (tetrahydrocannabivarine), which shows a 75% reduction in the potency to CB1 [66]. An increase in the number of carbon atoms (hexyl, heptyl, or octyl) leads to a respective increase in affinity and potency to interact with the cannabinoid receptors [70,71]. The length of the C-(3)-side chain of THC directly corresponds with CB1 and CB2 binding affinities, as an increase in chain length leads to an increase in binding affinity with the cannabinoid receptors [70]. Based on these ideas, various analogues of different carbon chains and rings, with or without heteroatom incorporation, may suggest the prediction of a SAR profile for a given structure, such as the THC scaffold. Besides the well-established study of the candidate target of SAR modulation based on the alkyl side chain, a number of other transformations in the tricyclic core of the cannabinoid structure have been carried out [72]. The cannabinoid compounds resulting from the pyran ring-opening reaction belong to the cannabidiol (CBD) derivatives, which demonstrate relatively low affinity to the CB1/CB2 cannabinoid receptors along with low psycho-activity [73]. Early SAR studies showed that the pyran ring in the cannabinoidic structure was not a requirement for cannabinergic activity in animal assays. However, several cannabidiol derivatives with high affinities for CB1 and CB2 receptors have been synthesized and thoroughly investigated [58]. Another possible structure modification on the THC scaffold is the C-(1) phenol group (Figure1). THC analogues that lack the phenolic hydroxyl group altogether, or even those exhibiting minor modifications to their phenolic group, may demonstrate drastic changes in their pharmacological abilities. It was recognized that CBD derivatives that experienced etherification or elimination of the phenol group displayed significant selectivity for CB2. The C-(11) is another major pharmacophore where minor structural changes can significantly modulate receptor binding (Figure2). Substitutions at this position do not confer selectivity when compared to analogues modified at the C-(1) phenol; however, the binding affinity may be greatly enhanced by this modification. ∆9-THC is an agonist for both CB1 and CB2 receptors. Its properties [74] were often overlooked due to its psychotropic side effects resulting from its activation of the CB1 receptor. This has limited the clinical application of the cannabinoid dual agonists, despite the multiple potential benefits for the treatment of neurodegenerative diseases, among others [75]. Therefore, the potential of synthesized cannabinoid analogues that may exploit the therapeutic effects of cannabinoids without Molecules 2018, 23, 1526 7 of 17 evoking the non-desired psychotropic properties is highly desired and extensive research in this direction is underway. Molecules 2018, 23, x FOR PEER REVIEW 7 of 16

Figure 2. Selected examples of common chemical modifications on tetrahydrocannabinol skeleton. Figure 2. Selected examples of common chemical modifications on tetrahydrocannabinol skeleton. Δ9-THC is an agonist for both CB1 and CB2 receptors. Its analgesic properties [74] were often 2.2. SARoverlooked of Cannabinoids due to its and psychotropic Their Receptors side effects in Treating resulting Neuronal from its activation Diseases of the CB1 receptor. This has limited the clinical application of the cannabinoid dual agonists, despite the multiple potential A possiblebenefits for prospect the treatment would ofbe neurodegenerative to study the SAR diseases, mechanism among ofothers synthesized [75]. Therefore, cannabinoids, the potential which do not evokeof synthesized the non-desired cannabinoid side effects analogues of that phytocannabinoids. may exploit the therapeutic This may effects be achieved of cannabinoids by the use of cannabinoidswithout that evoking would the non target-desired the CB2psychotropic receptor properties only, as is its highly activation desired does and extensive not lead research to psychotropic in side effectsthis direction and makes is underway it the. ideal target for the treatment of several neurodegenerative diseases including2.2. Parkinson’s SAR of Cannabinoids disease and (PD) Their [R76eceptors]. PD in is T areating chronic Neuronal disorder Diseases involving progressive degradation of the neuronal system and is the second most common neurodegenerative disease worldwide. A possible prospect would be to study the SAR mechanism of synthesized cannabinoids, which No therapies are currently available to cure PD. The symptomatic therapies available today only do not evoke the non-desired side effects of phytocannabinoids. This may be achieved by the use of improvecannabinoids patient quality that would of life target [77]. Inthe PD, CB2 dopamine receptor only, neurons as its activation of the substantia does not lead nigra to(i.e., psychotropic “black matter”) of the brainside effects degenerate and makes leading it the ideal to severe target for denervation the treatment of of the several striatum neurodegenerative that affect motor diseases activity. This irreversibleincluding Parkinson’s damage leads disease to the(PD) typical [76]. PD motor is a chronic symptoms disorder observed involvingin progressive patients sufferingdegradation from PD, includingof the bradykinesia, neuronal system rest and tremor, is the andsecond rigidity most common [77]. neurodegenerative disease worldwide. No Thetherapies cerebrospinal are currently fluid available of untreatedto cure PD. The PD symptomatic patients therapies was found available to today contain only highimprove levels of patient quality of life [77]. In PD, dopamine neurons of the substantia nigra (i.e.,“black matter”) of the endocannabinoidsbrain degenerate [78 ]. leading Administering to severe denervation inhibitors of of the endocannabinoid striatum that affect degradation motor activity. together This with a D2 dopamineirreversible receptor damage subtypeleads to the agonist typical reduced motor symptoms Parkinsonian observed motor in patients deficits suffering in in vivo frommodels PD, [79]. Furthermore,including an bradykinesia, increase in rest CB1 tremor, receptors and rigidity was [7 found7]. in the nigro-striatal lesion of PD patients, and in modelsThe of cerebrospinal nonhuman fluid primates of untreated [80]. Several PD patients clinical was studies found and to animalcontain highmodels levels suggest of that antagonistsendocannabinoids to the CB1 receptor [78]. Administ couldering have inhibitors value in of the endocannabinoid treatment of levodopa-induced degradation together dyskinesia with a and D2 dopamine receptor subtype agonist reduced Parkinsonian motor deficits in in vivo models [79]. PD symptoms, whereas agonists to CB1 receptor could prove useful in reducing levodopa-induced Furthermore , an increase in CB1 receptors was found in the nigro‐striatal lesion of PD patients, and dyskinesiain models [81]. of In nonhuman addition, primates a quinone [80]. Several derivative clinical of studies CBG and has animal recently models been suggest shown that to have neuroprotectiveantagonists activity to the CB1 against receptor inflammation-driven could have value in the neuronal treatment damageof levodopa in-induced an in vivo dyskinesiamodel of PD by the possibleand PD symptoms, involvement whereas of different agonists to binding CB1 receptor sites could at the prove PPAR usefulγ receptor in reducing [50]. levodopa Indeed,- it was demonstratedinduced indyskinesia a randomized, [81]. In addition double-blind,, a quinone placebo-controlled,derivative of CBG has recently crossover been clinical shown to trial have that the ,neuroprotective a cannabinoid activity receptor against agonist, inflammation significantly-driven neuronal reduces damage levodopa-induced in an in vivo model dyskinesia of PD by in PD the possible involvement of different binding sites at the PPARγ receptor [50]. Indeed, it was patients [82]. demonstrated in a randomized, double-blind, placebo-controlled, crossover clinical trial that the However,nabilone, thea cannabinoid CB2 receptor receptor may agonist, also significantly be important reduces in PDlevodopa treatment.-inducedCB2 dyskinesia was shownin PD to be upregulatedpatients in [82 glial]. elements in postmortem tissues of PD patients. Moreover, selective activation of CB2 receptors reduced pro-inflammatory mediators, confirming an inflammatory model and suggesting that CB2 may have an anti-inflammatory function in this disease [83]. Molecules 2018, 23, 1526 8 of 17 Molecules 2018, 23, x FOR PEER REVIEW 8 of 16

However, the CB2 receptor may also be important in PD treatment. CB2 was shown to be Oral administration of C. sativa extract to stimulate CB1 receptor activity was reported to cause upregulated in glial elements in postmortem tissues of PD patients. Moreover, selective activation of no improvementCB2 receptors in PD reduced symptoms pro-inflammatory [84], suggesting mediators, that cannabinoid confirming an activity inflammatory mayhave model to beand verified, which maysuggesting be accomplished that CB2 may have in two an anti ways.-inflammatory One would function be to in use this a disease combination [83]. of compounds from C. sativa to improveOral administration activity. Noteof C. sativa that extract the combination to stimulate CB1 of cannabis receptor-derived activity was compounds reported to cause is suspected to haveno a improvement synergic effect in PD [85 symptoms]. Another [84], option suggesting would that c beannabinoid to synthesize activity cannabinoidmay have to be analoguesverified, that may betterwhich bind may cannabinoidbe accomplished receptors, in two ways. preferably One would the be CB2.to use Indeed, a combination we acknowledge of compounds severalfrom C. efforts sativa to improve activity. Note that the combination of cannabis-derived compounds is suspected to that have been made in the design of CB2 selective derivatives [86] and in the understanding of their have a synergic effect [85]. Another option would be to synthesize cannabinoid analogues that may structure-activitybetter bind cannabinoid and structure receptors−affinity, preferably relationships the CB2. [Indeed,87]. we acknowledge several efforts that Inhave this context,been made scientific in the design research of CB2 is focusedselective onderivatives the development [86] and in the of molecularunderstand entitiesing of their with high affinitystructure for the– cannabinoidactivity and structure−affinity receptor CB2. relationships In recent years, [87]. a large number of CB2-selective synthetic compoundsIn aimed this context, at the scientific treatment research of neurodegenerative is focused on the development diseases have of molecular been developed entities with around high a wide affinity for the cannabinoid receptor CB2. In recent years, a large number of CB2-selective synthetic variety of (hetero)aromatic scaffolds. A detailed literature survey about the development of synthetic compounds aimed at the treatment of neurodegenerative diseases have been developed around a CB2 ligandswide variety was recently of (hetero)aromatic extensively scaffolds reviewed. A detailed [88]. CB2 literature selective survey derivatives about the havedevelopment been developed of startingsynthetic from mono- CB2 ligands or bicyclic was scaffoldsrecently extensively bearing heteroatoms, reviewed [88].bulky CB2 selective aliphatic derivatives or aromatic have carboxamide been groups,developed and either starting alkyl, from aryl mono or arylalkyl- or bicyclic substituents. scaffolds bearing Studies heteroatoms, focused onbulky the aliphatic research or ofaromatic the molecular unit responsiblecarboxamide for groups, the affinity, and either the selectivityalkyl, aryl or towards arylalkyl CB2substituents and the. S activitytudies focused profile on led the toresearch the design of a novelof CB2 the ligandmolecular for unit the responsible treatment for and the early affinity, diagnosis the selectivi of thety towards neurodegenerative CB2 and the activity diseases. profile led to the design of a novel CB2 ligand for the treatment and early diagnosis of the neurodegenerative 2.3. SARdiseases. and Activity Profiles of Several CB2 Selective Derivatives Several2.3. SAR (hetero)aromatic and Activity Profiles carboxamide of Several CB2 derivativesSelective Derivatives have been analyzed in terms of their SAR and activity profiles,Several including (hetero)aromatic oxoquinoline; carboxamide naphthyridinone; derivatives have quinolinedione;been analyzed in terms alkyloxycoumarin; of their SAR and indole; indazole;activity imidazopyridine; profiles, including imidazopyrazine; oxoquinoline; naphthyridinone benzimidazole;; quinolinedione purine; triazine;; alkyloxycoumarin pyridinone; biphenyl;; and prolineindole (Figure; indazole3).; imidazopyridine; imidazopyrazine; benzimidazole; purine; triazine; pyridinone; biphenyl; and proline (Figure 3).

Figure 3. The (hetero)aromatic carboxamide scaffolds investigated in their SAR (structure-activity

relationship) and activity profiles.

2.3.1. Oxoquinoline Several substituents on the 4-oxoquinoline structure have been investigated [89–92]. High CB receptor affinities may be attributed mainly to the alkyl linear chains at C-(1) position with the n-pentyl Molecules 2018, 23, 1526 9 of 17 group leading to the highest relative affinity to CB2. Bulky and lipophilic saturated-chain substituents of the 3-carboxamide functional group lead to high dual affinities. The highest affinity and selectivity for the CB2 receptor is achieved with an adamantyl ring. Substitution in the 6-position with aryl, alkyl, alkenyl, or alkynyl groups also lead to high selectivity for the CB2 receptor subtype [92].

2.3.2. Naphthyridinone 1,8-Naphthyridin-2(1H)-ones display high affinity for the CB2 receptor, which is strongly influenced by the N-(1) substituent, while the presence or the absence of an aryl substituent on the C-(6) confers a different activity profile [93–95].

2.3.3. Coumarin A series of coumarin derivatives have been designed on the basis of a Comparative Molecular Field Analysis (CoMFA) model and developed by Han et al. [96]. The best CB2R agonist activity (EC50(CB2) = 0.144 µM, CB1/CB2 selectivity ratio = 69.4) was found for 8-butyloxy substituted compounds on R1. The incorporation of the 3-carboxamide N-atom in a piperidine ring decreased agonist potency, indicating that the presence of a tertiary amide function leads to the loss of agonist activity.

2.3.4. Indole and Indazole SAR studies on indole derivatives revealed that among the N-indole carboxamide drugs the valinate and tert-leucinate methyl esters behave as potent agonists at CB1 and CB2 receptors. Recently, Longworth et al. [97] studied a series of 1-alkyl and 2-alkyl indazoles derivatives, where 1-alkyl isomers showed high CB1 agonist activity with nanomolar potencies (2.1−7.8 nM), where CB2 activity was less potent than CB1 activity. The 2-alkyl isomers displayed low potency towards both cannabinoid receptors.

2.3.5. Imidazopyridine and Imidazopyrazine These two series were tested towards both cannabinoid receptors and for their binding ability to plasma proteins. Imidazopyridines showed a higher agonist profile for the CB2 receptor than imidazopyrazine derivatives; moreover, the introduction of polar substituents in R2 increased the plasma protein binding ability. Overall, their potency for the CB2 receptor is modulated by modifications on the amide (R1) and amino (R2) functionalities [98].

2.3.6. Benzimidazole SAR studies on 2-arylmethyl or 2-aliphatic benzimidazole amides were performed [99]. Compounds bearing R1 = ethyl are more potent and more selective toward the CB2 receptor than N-unsubstituted derivatives. The derivative bearing a 2-chlorobenzyl substituent as R2 was the most potent compound toward the CB2 receptor, showing a 100-fold selectivity over the CB1 receptor. All the substitutions on the aryl in R2 led to an overall decrease of potency for the CB2 receptor and to the loss of CB1 receptor activity.

2.3.7. Purine Purinic ligands are potent CB2 agonists and show an excellent selectivity toward the CB1 receptor with good pharmacodynamic and pharmacokinetic profiles and water solubility [100].

2.3.8. Triazine Trisubstituted 1,3,5-triazines were identified as potent CB2 agonists by 3D ligand-based virtual screening. Several CB1 receptor antagonists or inverse agonists and CB2 agonists were developed, Molecules 2018, 23, 1526 10 of 17 and the most potent derivatives of the series were identified in N-(adamantan-1-yl) substituted compounds with EC50 values up to 0.60 nM [101].

2.3.9. Proline Several proline derivatives were identified by a computer assisted drug design (CADD) approach based on a well-known series of CB2 receptor ligands by Hickey and co-workers [102]. Several (S)-isomers showed full CB2 agonist activities with high potencies (picomolar range) and a CB2/CB1 selectivity ratio higher than 750, while the corresponding (R)-isomers displayed a partial agonist profile with lower potencies toward the CB2 receptor. Several proline derivatives bearing different R1 and R2 substituents were also developed: hydroxyproline derivatives showed high CB2 potency and selectivity as well as the highly water-soluble δ-oxoproline derivatives; the latter demonstrated high metabolic stability.

2.3.10. Pyridinone Developed derivatives of 2-pyridinone showed high CB2 selectivity and affinity when N-substituted on the carboxamide with a large cycloalkyl ring, while substituent on the C-(5) was found pivotal for the activity profile [103].

2.3.11. Biphenyl SAR studies carried out on biphenylic carboxamides showed once more that a large cycloalkyl ring (cycloheptyl) on the carboxamide function improves affinity and selectivity for the CB2 receptor, while substituents in C-(5) and C-(40) are mainly responsible for the activity profile [104,105]. In summary, oxoquinoline (Figure4a), 1,8-naphthyridin-2(1 H)-one (Figure4b), 2-pyridinone (Figure4c), and biphenyl (Figure4d) scaffolds have shown the highest affinity toward a CB2 receptor subunit. An analysis of the common structural features of these compound classes reveals that high selectivity toward the CB2 receptor requires the presence of a carbonyl group and a carboxamide function linked to a cycloalkyl ring. Moreover, functionalization of the C-1 position and the presence of a nitrogen atom in the cycloalkyl ring improve the affinity, while the presence of a bicyclic ring is not mandatory to achieve good selectivity to CB2. Moreover, minor modifications of the cannabinoid structures has a dramatic effect on the pharmacological behavior of these compounds, switching the profile from being an agonist to inverse agonist or antagonist activity [88]. Molecules 2018, 23, x FOR PEER REVIEW 10 of 16

Purinic ligands are potent CB2 agonists and show an excellent selectivity toward the CB1 receptor with good pharmacodynamic and pharmacokinetic profiles and water solubility [100].

2.3.8. Triazine Trisubstituted 1,3,5-triazines were identified as potent CB2 agonists by 3D ligand-based virtual screening. Several CB1 receptor antagonists or inverse agonists and CB2 agonists were developed, and the most potent derivatives of the series were identified in N-(adamantan-1-yl) substituted compounds with EC50 values up to 0.60 nM [101].

2.3.9. Proline Several proline derivatives were identified by a computer assisted drug design (CADD) approach based on a well-known series of CB2 receptor ligands by Hickey and co-workers [102]. Several (S)-isomers showed full CB2 agonist activities with high potencies (picomolar range) and a CB2/CB1 selectivity ratio higher than 750, while the corresponding (R)-isomers displayed a partial agonist profile with lower potencies toward the CB2 receptor. Several proline derivatives bearing different R1 and R2 substituents were also developed: hydroxyproline derivatives showed high CB2 potency and selectivity as well as the highly water-soluble δ-oxoproline derivatives; the latter demonstrated high metabolic stability.

2.3.10. Pyridinone Developed derivatives of 2-pyridinone showed high CB2 selectivity and affinity when N- substituted on the carboxamide with a large cycloalkyl ring, while substituent on the C-(5) was found pivotal for the activity profile [103].

2.3.11. Biphenyl

Molecules 2018, 23SAR, 1526 studies carried out on biphenylic carboxamides showed once more that a large cycloalkyl 11 of 17 ring (cycloheptyl) on the carboxamide function improves affinity and selectivity for the CB2 receptor, while substituents in C-(5) and C-(4′) are mainly responsible for the activity profile [104,105].

Figure 4. The (hetero)aromatic compounds which exhibit the highest affinity for CB2 receptors based on (a) oxoquinoline, (b) 1,8-naphthyridin-2(1H)-dione, (c) 2-pyridinone and (d) biphenyl structures.

3. Conclusions Studies of the mechanisms controlling neurodegenerative diseases, together with systematic observations of the cannabis treatments given to patients with neurodegenerative diseases, led to the recognition of the beneficial effect of cannabinoids on these illnesses. However, the very complicated assemblage of secondary metabolites in C. sativa extracts, together with the non-desired psycho-reaction accompanying cannabis use, led to the appreciation of the importance of the structure-activity relationship. SAR studies are essential to synthesize an appropriate cannabinoid with high therapeutic availability and low psycho-activity. The potency of CBD was marked as it has relatively low psychoactivity due to its low affinity to the CB1 receptor. In this paper, we show that different minor manipulations of the CBD structure may increase its affinity and binding ability to CB2. We also show that CB2 activation is involved in neurodegenerative conditions, such as PD, and thus activation of the CB2 receptor may be developed as a treatment for PD patients. The study of the SAR mechanisms between cannabinoids and their receptors, as well as the design of targeted cannabinoids-like compounds with higher SAR abilities, along with the understanding of CB2 enhanced reception role, put SAR studies at the cutting-edge in C. sativa studies and should be further investigated and clinically tested.

Author Contributions: Conceptualization, H.K. and C.P.; Writing-Original Draft Preparation, H.K., C.P., D.N. and M.B. Funding: This research was funded by MIUR (Italian Ministry for University and Research) and Fondazione CRT, C.P. Article processing charge was sponsored by MDPI. Conflicts of Interest: The authors declare no conflict of interest.

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