Volume 60 2013 Number 1 JOURNAL of the BULGARIAN

Volume 60 2013 Number 1

JOURNAL OF THE BULGARIAN PHARMACEUTICAL SCIENTIFIC SOCIETY

Editorial Board:

Alexander Zlatkov (Faculty of Pharmacy, MU, Sofia, Bulgaria) Christo Tzachev (Faculty of Pharmacy, MU, Sofia, Bulgaria) Christo Tsvetanov (Institute of Polymers, BAS, Sofia, Bulgaria) Darvin Ivanov (Faculty of Pharmacy, MU, Sofia, Bulgaria) Danka Obreshkova (Faculty of Pharmacy, MU, Sofia, Bulgaria) Georgi Momekov (Faculty of Pharmacy, MU, Sofia, Bulgaria) Guenka Petrova (Faculty of Pharmacy, MU, Sofia, Bulgaria) Ilijana Jonkova (Faculty of Pharmacy, MU, Sofia, Bulgaria) Jasmina Tencheva (Faculty of Pharmacy, MU, Sofia, Bulgaria) Nikolai Lambov (Faculty of Pharmacy, MU, Sofia, Bulgaria) Nikolai Danchev (Faculty of Pharmacy, MU, Sofia, Bulgaria) Stefan Nikolov (Faculty of Pharmacy, MU, Sofia, Bulgaria) Bistra Angelovska (Goce Delcev University, Skopje, Macedonia) Ebba Holme Hansen (University of Københavns, København, Denmark) Fabrice Clerfeuille (University of Nantes, Nantes, France) Georg Heun (University of Applied Sciences, Koetten, Germany) Luisa Pistelli (University of Pisa, Pisa, Italy) Marion Schaefer (Institute of Clinical Pharmacology and Toxcology, Berlin, Germany) Mecedes Unzeta (Autonomic University of Barselona, Barcelona, Spain) Ruediger Groening (University of Muenster, Muenster, Germany) Svjetlana Luterotti (University of Zagreb, Zagreb, Croatia) Danijel Kikelj (University of Ljubljana, Ljubljana, Slovenia)

Editor in Chief: P. Peikov

Secretary: M. Georgieva

Indexed in: MEDLINE, CAplusSM/Chemical Abstracts, TOXCENTER, EMBASE/Excerpta Medica, PASCAL, BIOTECHNOBASE, ExtraMEDTM, SCOPUS

Editorial/publishing policy: Manuscripts submitted to PHARMACIA are only accepted on the understanding, that they are subject to editorial review and review of at least two independent referees, that they have not been and will not be bublished whole or in part in any other journal and that recommendations to comply with with ethycal standards when performing clinical and other biological experiments have been adhered to. Publishing frequency is four times a year (volume). Only abstracts published in the Journal may be reproduced without prior permission; reproduction of other materials requires publisher’s consent.

Address of Editorial Board

Faculty of Pharmacy Editor in Chief: (+359 2) 9236 505 2, Dunav str., Sofia 1000 E-mail: [email protected] Fax (02) 987 987 4 Secretary: (02) 9236 515: E-mail: [email protected] PPHHAARRMMAACCIIAA

Volume 60 2013 Number 1

C O N T E N T S

Original articles I. Todorov, M. Christov, K. Stanoeva, K. Yakimova. Leptin and GABA interactions on body temperature of rats ...... 3

S. Harkov, D. Havrylyuk, V. Atamanyuk, B. Zimenkovsky, R. Lesyk. Synthesis and biological activity of isatines bearing thiazolidinone and pyrazoline moieties ...... 8

L. Peikova, B. Tsvetkova. RP-HPLC method for simultaneous determination of Amlodipine besylate and Valsartan in pharmaceutical dosage form ...... 19

Review articles Georgi Momekov, Niko Benbassat. Pharmacological properties of Hawthorn leaf and ﬂ ower as a cardiovascular agent ...... 24

L. Peikova, B. Tsvetkova. Amide-based prodrugs of nonsteroidal anti-inﬂ ammatory drugs ...... 37

L. Andonova, M. Georgieva, Al. Zlatkov. Arylpiperazine derivatives – new agents affecting mood disorders...... 46

Georgi Momekov, Iliana Ionkova, Paraskev Nedialkov, Zlatina Kokanova-Nedialkova, Dimitrina Zheleva-Dimitrova, Ilina Krasteva, Yohana Ilieva, Ilina Dineva, Gerassim Kitanov, Stefan Nikolov, Spiro Konstantinov. Overview of the oncopharmacological studies of plant-derived natural products conducted at the Faculty of Pharmacy (MU-Soﬁ a) ...... 60

D. Obreshkova. Reactive oxygen species induced neurodegeneration in Alzheimer’s disease ...... 71

From the Editorial board Instructions to authors ...... 83 46 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov

ARYLPIPERAZINE DERIVATIVES – NEW AGENTS AFFECTING MOOD DISORDERS

L. Andonova, M. Georgieva, Al. Zlatkov Department of “Pharmaceutical chemistry”, Faculty of Pharmacy, Medical University, Soﬁ a

Abstract. Disorders of the central nervous system currently affect over 1.5 billion people worldwide and account for about a third of the global disease burden. The prevalence in recent years and the variety of mood disorders stimulate the development of new agents for their treatment. 1-Arylpiperazines are well known 5-HT receptor ligands with

5-HT1A and/or 5-HT2A afﬁ nity. The inclusion of a complex heterocyclic fragment through a poly-

methylene spacer at piperazine position N4 often leads to more potent ligands in both 5-HT1A and

5-HT2A afﬁ nities. The results described in literature permit an assumption that the structure of the substituent in positions 1 and 7 of purine-2,6-dione may be regarded as important factor involved

in the control of 5HT1A afﬁ nity. From the presented investigations may be concluded, that the

modiﬁ cation within the aryl fragment had typical inﬂ uence on 5-HT1A receptor activity. Substi- tutents at the ortho position of the phenyl ring are well accepted, and the respective analogues

always display higher 5-HT1A afﬁ nity than the unsubstituted phenylpiperazines.

Key words: mood disorders, antidepressants, 5-HT1A / 5-HT2A receptor antagonists

Introduction and dysthymia, are among the most prevalent men- Human’s nervous system consists of central nerv- tal disorders. Depressive disorders affect individu- ous system (CNS) and peripheral nervous system als across all age groups, including children and the (PNS). CNS is the largest part, and includes brain aged [5]. and spinal cord. The nerve cells (neurons) are ‘excit- According to the World Health Organization able’ and can transduce a variety of stimuli into elec- (WHO), MDD will be the most prevalent cause of trical signals. The junctions between neurons (syn- illness-induced disability by the year 2030. The dis- apses) are electrical or chemical. The former permit ease is supposed to result from a complex interaction the direct transfer of electrical current between cells, of genetic and epigenetic, environmental and devel- whereas the latter utilize chemical signaling mol- opmental factors. However, the molecular mecha- ecules (neurotransmitters) to transfer information be- nisms underlying this disease are still largely unclear. tween cells. Neurotransmitters are mainly amino ac- Identifying new drug targets and thereby developing ids (GABA, glutamate and aspartate), neuropeptides, more effective treatments are primary goals of re- purines (adenosine, adenosine mono- and triphos- search in that ﬁ eld. To achieve these goals a greater phate) or amines (acetylcholine, catecholamines, epi- understanding of the etiology of MDD is needed, nephrine, norepinephrine, dopamine; and 5-hydroxy which involves identifying the risk and resilience triptamine (5-HT or serotonin)) and can be excitatory factors involved and the mechanisms by which these or inhibitory [1-3]. effects are mediated [6]. Disorders of the central nervous system currently A great number of contemporary diseases are affect over 1.5 billion people worldwide and account due to dysfunction of the receptors of 5-HT and do- for about a third of the global disease burden. But this pamine [4]. considerable healthcare challenge is set to increase Alterations in the brain monoamines dopamine substantially in the decades ahead as, making CNS (DA) and serotonin (5-HT) have been implicated disorders a major medical need of the 21st century [4]. in the etiology and/or pharmacotherapy of multiple Mood disorders, especially unipolar depressive mental disorders including schizophrenia and de- disorders, such as major depressive disorder (MDD) pression [7]. Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 47

Serotonin as neurotransmitter ptosis and platelet aggregation. Serotonin is actively Serotonin also known as 5-hydroxytryptamine (5- taken up by cells expressing the Na+/Cl- dependent HT) is a biogenic amine that functions as a ligand for serotonin transporter (SERT) where it is stored in in- a large family of 5-HT receptors [8]. The majority of tracellular vesicles and released in response to various serotonin in the body (90%) is synthesized by entero- stimuli. Once bound to target receptors or taken up by chromafﬁ n cells of the gastrointestinal (GI) tract and the SERT, serotonin can be metabolized by monoam- from here it is exported to various sites around the ine oxidase (MAO) leading to the generation of 5-hy- body. Serotonin plays a major role in neurotransmis- droxyindoleacetaldehyde (5-HIAA) [9]. sion within the central nervous system (CNS) and the Fig. 1 gives an overview of the intermediate com- autonomic nervous system (ANS). In the CNS sero- pounds and enzymes involved in serotonin synthesis tonin is known to control mood, behavior, perception, and metabolism. pain, learning, sleep and anxiety. Peripherally, seroto- The family of receptors that bind serotonin is sub- nin is able to mediate vascular contraction and relaxa- divided into seven subgroups and where appropriate tion, gastrointestinal motility, cell proliferation, apo- these subgroups are further divided (Table 1).

Serotonin Synthesis

Tryptophan 5-hydroxy-L-tryptophan Serotonin H H H +THB OH-THB N N CO2 N +O2 NH2 NH2 TH OH HO OH AADC HO NH2 O O

Receptor Binding

Release Into the Vesicle Storage Internallisation extracellulaer millieu

Uptake by the SERT

H O NAD+ NADH 2 H2O2 H H O H+ H N 2 N H2O N OH MAO AD (NAD) HO HO O HO NH2 O Serotonin 5-hydroxyindolacetaldehyde 5-hydroxyindolcetate

Serotonin Metabolism

Fig.1. Serotonin synthesis and metabolism. 48 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov

Table 1: Summary of human 5-HT receptor characteristics Human Agonist Antagonist G protein Common Functions receptor coupling signaling linkage

5-HT1A 8-OH-DPAT, buspirone, WAY 100635, Gi/o Inhibits AC, CNS: neuronal 5-HC methiothepin, spiperone Activates K+ hyperpolarisation channels, Stimulates ERK

5-HT1B 5-HC, CP 93129, SDZ 21009, methiothepin, Gi/o Inhibits AC, CNS: inhibition of sumatriptan yohimbine Stimulates neurotransmitter release ERK

5-HT1D Sumatriptan, L 694247, Metergoline, methiothepin, Gi/o Inhibits AC CNS: inhibition of 5-HC GR 127935 neurotransmitter release

5-HT1E 5-HT Methiothepin Gi/o Inhibits AC Not yet characterised

5-HT1F 5-HT Methiothepin Gi/o Inhibits AC Not yet characterised

5-HT2A α – Methyl-5-HT, DOI Ketanserin, ritanserin, Gq Activates CNS: neuronal excitation; pirenperone PLC&PKC, periphery: smooth muscle Stimulates contraction, petelet ERK, aggregation Activates PLA2

5-HT2B α – Methyl-5-HT, DOI SB 200646, LY 53857 Gq Similar to Periphery: GI motility

5-HT2A

5-HT2C α – Methyl-5-HT, DOI Mesulergine, ritanserin, Gq Similar to CNS: cerebrospinal ﬂ uid

LY 53857 5-HT2A secretion

5-HT3 2 – Methyl-5-HT, Ondasetron N/A Peripheral and central m-chlorophenylbiguanide neurons: depolarization

5-HT4 Metoclopramide, Tropisetron Gg Activates CNS: neuronal excitation; renzapride AC&PKA Periphery: GI motility; tachycardia

5-HT5A 5-HT, 5-CT Methiothepin Unknown Unknown Not yet characterised

5-HT5B 5-HT Methiothepin Unknown Unknown Not yet characterised

5-HT6 5-HT, LSD SB 271046 Gg Activates CNS: unknown AC&PKA

5-HT7 5-HT, LCD, 5-CT Methiothepin Gg Activates CNS: unknown; AC&PKA Periphery:unknown

5-CT, 5-carboxamidotryptamine; 5-HT, 5-hydroxytriptamine; 8-OH-DPAT, 8-hydroxy-2-di-n-propylamino-tetralin; AC, adenylate cyclase; DOI(+-)-[(1-(2,5-dimethoxy-4-iodophenyl)-aminopropane)hydrocloride]; ERK, extracellular regu- lated kinase; GI, gastrointestinal; LCD, lysergic acid diethylamide; PKA, protein kinase A; PKC, protein kinase C; PLA, phospholipase A; PLC, phospholipase C Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 49

Table 1 summarizes the characteristics associated new application. This meta-triﬂ uorophenylpipera- with each member of the human serotonin receptor zine derivative, classiﬁ ed as a 5-HT1A agonist and family. These receptors have been grouped accord- 5-HT2A antagonist, had initially been developed as ing to their genetic and structural similarities and also an antidepressant [13,14]. Later it was found that according to the intracellular signaling pathways as- it exerts potential antipsychotic effects. It has also sociated with each receptor. All members of the sero- been investigated as a drug for women with de- tonin receptor family are linked to G-proteins, except creased sexual desire [15]. the 5-HT3 receptor which is a ligand-gated Na+/K+ Currently in the treatment of general mood disor- channel [10]. ders a number of arylpiperazine derivatives are ap- While all 5-HT receptor subtypes are localized plied with main activity directed to 5-HT receptors. postsynaptically on 5-HT target cells, the 5-HT1A Thus Etoperidone, Nefazodone and Trazodone (Fig. and 5-HT1B/D subtypes are located presynaptically on 2), antidepressants of the phenylpiperazine class,

5-HT neurons. In the raphe nuclei, 5-HT1A receptors act primarily as an antagonists of several receptors are localized on 5-HT cell bodies and dendrites where in the following order of potency: 5-HT2A receptor they function as auto receptors. 5-HT is released so- > 5-HT1A receptor [16,17]. Nefazodone has a some- matodendritically and decreases 5-HT cell fi ring by what higher affi nity for 5-HT2A receptors compared activating these receptors [7]. to 5-HT2C receptors [17], while preclinical and clini- Thus in the 1960s and 1970s it was reported that cal data suggest that Trazodone acts as an antidepres- depressed patients had reduced 5-HT binding sites sant via antagonist action at 5-HT2/1C receptors [18]. on platelets and low 5-HT metabolite levels in cer- It was also found that Trazodone in low doses will ebrospinal fl uid. Interestingly, this effect was ob- only act via the most potent binding properties, but served in patients with a history of depression even higher doses recruit additional pharmacologic ac- when recovered and off drug treatment, suggesting tions and become “multifunctional” with a different a link between reduced 5-HT function and depres- mixture of pharmacologic functions, depending upon sion vulnerability, and not just the acute depressive how high a dose is given [19]. As it seem, Trazodone state. The neuroendocrine data accord with more is a good example of a dose dependent multifunction- recent fi ndings from positron emission tomography al drug in psychopharmacology. It is noteworthy that

(PET) studies, of a widespread decrease of 5-HT1A phenylpiperazine fragment in these three products is receptors in the brains of acutely depressed patients substituted on third place in the aromatic system. as well as patients who have recovered. Other PET Piberaline is a psychoactive drug and member of studies have investigated the 5-HT2A receptor and the benzylpiperazine class which has stimulant and 5-HTT in depressed patients, but ﬁ ndings to date antidepressant effects which are thought to be due are inconsistent. If anything, 5-HT2A receptor bind- largely to its active metabolite benzylpiperazine [20]. ing is increased in the cortex of both depressed and recovered subjects, and this neurochemical change Cl N N N N correlates with measures of negative beliefs about H3C N NN N N Cl N the self and the world [11]. H3C O O Trazodone The 5-HT receptors are to date one of the best O 1A Etoperidone N characterized subtypes and it is generally accepted N N H C N N Cl that they are involved in psychiatric disorders such 3 Piberaline NN N O O as depression and anxiety [12]. N O N (CH2)4 N N N Nefazodone N O Buspirone Arylpiperazine based drugs used in depression CF3 O O N N treatment S N CH2 CH2 NN N N

The prevalence in recent years and the variety of N O Ipsapirone O Flibanserin mood disorders stimulate the development of new H agents for their treatment. Arylpiperazines are valu- able investigative tools in neuropsychopharmacology Fig.2. Chemical structure of arylpiperazine based drugs and have the potential to be leads in the development used in depression treatment of new therapeutic agents. Flibanserin (Fig. 2) is an excellent example of a When the phenyl ring in 1-phenylpiperazine classic long-chain arylpiperazine with an interesting fragment was replaced with 2-pyrimidine, the an- 50 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov tidepressive activity remains. Thus buspirone and ipsapirone (Fig. 2) are effective antianxiety and antidepressant drugs [21]. The reported studies on the structure-afﬁ nity relationship of the 1-arylpiperazines indicate that the terminal amide fragment in buspirone-like ligands stabilize the 5-HT1A receptor-ligand complex by ei- ther p-electron or local dipole-dipole interaction [23]. Also, the results show that the basic nitrogen atom and terminal, bulky cycloimide moiety, but not the 2-pyrimidinyl group of buspirone, are directly involved in the formation of the bioactive complex with 5-HT1A receptor [24].

Current trends in arylpiperazine derivatives as Fig.3. Structure of 5-HT receptor serotonine antagonists (from http://www.cnsforum.com/content/pictures/image- As a superior goal of a great number of studies bank/hirespng/5HT_struc_level2.png) in the fi eld of medicinal chemistry is the search for selective model compounds that would serve as tools to investigate ligand–receptor interactions. Several pyrrolidine-2,5-dione, as a terminal imide, with a 4-ar- compounds from different chemical classes possess ylpiperazine moiety connected to the amide fragment high affi nity for 5-HT receptors.[21] Molecules 1A with a alkylene spacer. All compounds were tested for based on arylpiperazine core were classifi ed as li- their 5-HT /5-HT receptor affi nity (Fig. 4). gands of serotonin (5-HT), α-adrenergic or dopamine 1A 2A receptors and some of them became clinically use- O ful drugs in the treatment of anxiety, depression and R psychosis as well as other psychiatric disorders [22]. A . HCl Long chain arylpiperazines (LCAPs) are one of N (CH2)n NN the largest and most diverse classes of compounds O exerting actions on the central nervous system [23]. Structure-activity relationship studies in the fi eld of ring A = cyclohexane, 2-methylcyclohexane, cyclopentane, tetralone LCAPs, investigated as serotonin receptor ligands, R = H, 2-F, 3-Cl, 2-OCH3, n = 0,1, 2, 3 have at least a 20-year history. The majority of new derivatives have been designed basing on buspirone Fig. 4. Structure of 3-spiro-substituted pyrrolidine-2,5-dion structure by modifi cation of its three main fragments. Their general chemical structure consists of the aryl- For the series with propylene spacer the authors piperazine moiety connected by an alkyl chain with comment only the infl uence of amide/imide moiety the terminal amide or imide fragment. Of the three over the receptor activity. The results of radioligand structural elements mentioned above, a less clear binding studies show different 5HT1A/2A receptor is, however, the function of a terminal imide/amide binding and indicate that introduction of spirocy- group. It is postulated that this part of the ligand is clohexyl moiety increased the receptor affi nity, espe- located in a large pocket formed by helices IV–VI cially towards 5-HT2А receptor subtype in compari- (Fig. 3), where different forces are engaged in stabi- son with previously obtained 3-phenyl derivatives. lizing the ligand-receptor complex. It is worth to note Additionally, it seems that introduction of a supple- that the limit of hydrophobic pocket capacity is very mentary aromatic ring to the spirocyclohexyl moiety important [25]. did not change 5-HТ1А but decreased 5-HT2A receptor Although the role of the respective elements of affi nity. This suggests that the 3-spirocyclohexane LCAPs was a subject of earlier studies [26-28], new ring in pyrrolidine-2,5-dione is tolerated better than modifi cations still result in obtaining compounds β-tetralone fragment at 5-HT2A binding sites [22]. presenting interesting pharmacological properties. For the series of N-[(4-arylpiperazin-1-yl)-alkyl]- Jolanta Obniska et al. [29-32] obtained several 2-azaspiro[4.4]nonane and [4.5]decane-1,3-dione groups of LCAPs with 3-spirocycloalkyl-substituted derivatives with the methylene spacer [31-32] was Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 51

found that they exhibited low 5-HT1A/5-HT2A recep- the structure–activity relationships in arylpiperazine tor afﬁ nity, in contrast to their ethylene analogues group of serotonin ligands, Bojarski et al. [36] synthe- regarded as potent 5-HT1A ligands, especially those sized some new derivatives containing quinazolidin- containing a cyclohexane moiety in the 3-position 4(3H)-one, 2-phenyl-2,3-dihydrophthalazine-1,4- of the pyrrolidine-2,5-dione ring. All of these results dione and 1-phenyl-1,2-dihydropyridazine-3,6-dione suggested a crucial role of the spacer between the fragments (Fig. 6). Seven of the tested compounds amide fragment and 4-arylpiperazine moiety, as well showed a high afﬁ nity for 5-HT1A receptors and two as of the size of the cycloalkyl ring at the 3-position were found active at 5-HT2A sites. All new 5-HT1A li- of pyrrolidine-2,5-dione ring in functional 5-HT1A/5- gands tested in vivo revealed an antagonistic activity

HT2A properties. at postsynaptic 5-HT1A receptors, and three of them Hanna Byrtus et al. discussed the inﬂ uence of behaved as agonists at presynaptic ones. substitution mode in phenyl ring of phenylpiperazine moiety of a series of compounds given on Fig. 5 on R the afﬁ nity for both receptors. 1 N(CHN 2)n R

R = 3-Cl, 2-OCH3, O n = 3, 4 N R O O N (CH2)3 N N N HN R = N N O O N N

O O R=H, o-OCH3, m-Cl, o-F, p-F, m-CF3

Fig. 5. Structure of LCAPs with different substituent in Fig. 6. Structure of LCAPs derivatives containing quina- phenyl ring of phenylpiperazine moiety zolidin-4(3H)-one, 2-phenyl-2,3-dihydrophthalazine-1,4- dione and 1-phenyl-1,2-dihydropyridazine-3,6-dione frag- The investigated compounds exhibit moder- ments. ate to low in vitro activity for 5-HT1A receptors. It has been expected that an introduction of o-OCH3, Also, both the meta-chlorophenylpiperazine de- m-Cl, m-CF3 and o-F substituents should enhance rivatives containing quinazolidin-4-one fragment the 5-HT1A in vitro activity of respective analogues showed features of 5-HT2A receptor antagonists. The of the unsubstituted derivative. This effect has been dual 5-HT1A/5-HT2A receptor ligand (n = 4) was fur- observed only for m-CF3 derivative, whereas o- ther tested for its potential psychotropic activity. It

OCH3 and m-Cl groups produced a slight decrease showed a distinct anxiolytic-like activity. in the 5-HT1A affi nity. Unexpectedly, the compound Jerzy Kossakowski et al. investigated a series of with o-F substituent was six times less potent than new derivatives with two imide terminals (Table 2). the unsubstituted phenylpiperazine. In the case of p-F To explore the infl uence of the bulky fragment on analogue a substantial decrease in the 5-HT1A affi n- the serotonergic activity, the most thoroughly stud- ity was observed, which is in agreement with previ- ied arylpiperazines (phenyl-, 2-hydroxyphenyl-, ously published data [33], that substituents in para 4-fl uorophenyl-, 2-methoxyphenyl-,2-pirymidyl-,2- position (with different electronic properties) caused pirydyl-) and a standard spacer chain (three or four- unfavorable steric interactions with the 5-HT recep- unit) were applied. tor binding side. With regard to the 5-HT2A receptors, Although the investigated compounds did not re- the o-OCH3 group exerted the most negative effect veal high pharmacological activity, their examination on the affi nity, however the presence of m-Cl and provided useful data for defi ning the volume of the p-F substituents enhanced it and these results are in 5-HT1A receptor hydrophobic pocket. The results in- line with the recently published investigations [34]. dicate that bulky imide fragments can be well toler-

On the contrary, affi nity of m-CF3 derivative was ated when combined with favorable components, i.e. decreased by two times in comparison to the par- a longer chain and/or an o-methoxyphenylpiperazine ent compound. On the basis of systematic studies on fragment. The results obtained for some of the inves- 52 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov tigated compounds suggest that the volume of ap- sized and evaluated as 5-HT receptor ligands. Some 3 proximately 300 Å can be regarded as a limit of the of them demonstrated signifi cant affi nity for 5-HT1A

5-HT1A receptor binding region responsible for inter- and/or 5-HT2A receptors and were extensively studied actions with the amide/imide fragments of LCAPs. as antidepressant agents [37]. Maria J. Mokrosz et al. synthesized three series Table 2. Structure of LCAPs with bulky imide terminal of new unsubstituted or 2-acyl 1,2,3,4-tetrahydro-β- fragment carbolines (THBC), connected to 1-(o-methoxyphenyl) piperazine by 2-, 3- or 4-membered alkylene R1 N spacer in position 9, and their 5-HT1A/5-HT2A recep- N tor afﬁ nities and functional in vivo activities were in- R-(CH ) 2 n vestigated (Fig. 7).

RnR1

O N R OCH3 O N phenyl- N 2-hydroxyphenyl- 4 N N (CH )n O 4-ﬂ uorophenyl- 2 2-methoxyphenyl- 2-pirymidyl- 2-pirydyl- n=2,3,4; R=hydrogen, acetyl, acryloyl, benzoyl, cyclohex- ylocarbonyl, phenylacetyl O 3 Fig. 7. Structure of LCAPs with different length of the H3C alkylene space O N The obtained results indicated that the length of an O alkylene chain is a crucial parameter for determining

5-HT1A receptor afﬁ nities of the tested compounds. CH3 Derivatives with prop-1,3-ylene and particularly

with but-1,4-ylene spacer had a high 5-HT1A recep-

tor affi nity, whereas the 5-HT1A affi nity of derivatives with ethylene spacer was low. All those compounds From the performed investigations may be con- did not distinctly bind to 5-HT receptors [38]. cluded, that the modifi cation within the aryl fragment 2A Tetrahydro-γ-carbolines (THGCs) were defi nite- had typical infl uence on 5-HT receptor activity. Sub- 1A ly less extensively explored than β -analogues, and stitutents in the ortho position at the phenyl ring were relatively little is known about their 5-HT binding well accepted, and the respective analogues always profi le. Indeed, besides 5-HT affi nity and some ex- displayed higher 5-HT affi nity than did unsubsti- 2A 1A amples of 5-HT antagonistic properties detected for tuted phenylpiperazines. The contrary was observed 3 γ-carbolines (Alosetron) [39], other types of seroto- for p-F derivatives which were the least active in each ninergic activity are diffi cult to fi nd. Only recently series. With regard to 5-HT receptors, moderate ac- 2A some THGCs have been described as 5-HT recep- tivity was found for two derivatives only [25]. 5A tor ligands [40]. To the best of our knowledge, the Compounds containing a carboline ring system binding of γ-carboline derivatives to 5-HT recep- belong to a large family of biologically active indoles 1A tors has not been reported so far. which are very important to the function of the cen- Jan Boksa et al. synthesized a series of 15 new tral nervous system. Of the four classes of carboline 2-H and 2-substituted derivatives of THGC, based on derivatives (α, β, γ, and δ), β-carbolines are the most some previous investigations, in which β-carboline thoroughly investigated due to their wide occurrence and arylpiperazine moieties resulted in several potent in nature (i.e. in plant alkaloids, endogenous human 5-HT and/or 5-HT ligands. The combination of substances) and diversifi ed pharmacological effects. 1A 2A THGCs with a 2-methoxyphenylpiperazine fragment A number of tetrahydro-β-carbolines were synthe- Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 53

suggests to prefer the 5-HT1A binding sites. Thus the the serotonin receptors, but its role is still unclear. It both pharmacophoric groups were linked via an alkyl has been shown that lipophilicity or the dipole mo- spacer of different length (2–4 units), and general- ment of the terminal amide or cycloamide fragments ly the new compounds can be regarded as LCAPs, of 1-arylpiperazines signifi cantly affect the 5HT1A/2A where a γ-carboline core plays a role of a complex receptor affi nities [41-43]. terminal fragment (Fig. 8). Additional structural The results described in literature permit an as- modifi cation has been restricted to R substituents at sumption that the structure of the substituent in N2 of the THGC moiety. position 7 of purine-2,6-dione may be regarded as

important factor involved in the control of 5HT1A afﬁ nity [44]. R Tricyclic theophylline derivatives, annelated six N or seven- membered heterocyclic ring at 7,8-position of theophylline, generally demonstrated a dif- N ferent proﬁ le of its central nervous system activity,

(CH2)n in comparison to the reference compound (theo- N phylline). The pharmacological evaluation of a series of tricyclic theophylline derivatives with a pyrimido- or diazepino-moiety demonstrated their N sedative, hypothermizing and neuroleptic-like ef- OCH3 fects on the CNS. Agnieszka Zagorska et al. synthesized series of N-8-arylpiperazinylpropyl derivatives of imidazo[2,1-f]purine-2,4-dione and amide deriva- n=2,3,4; R = H, CH3, CH2C6H5, COCH3, COC6H5 tives of 6,7-dihydroimidazo[2,1-f]purine-2,4-dione- 7-carboxylicacid (Fig. 9). Fig. 8. Structure of 2-H and 2-substituted derivatives of THGC

R1 The results of the in vitro examination for their af- O R fi nity for 5-HT1A/2A receptors has indicated that most CH3 N N of them are potent 5-HT1A receptors ligands. Gener- N N N ally, the lowest affi nity for 5-HT1A receptors has been detected for compounds with a dimethylene spacer, O N N with the exception of acetyl derivative. The spacer CH3 elongation by one methylene unit resulted in a signifi cant increase in the observed in vitro activity. It is R1 worth to note that in the case of the previously studied

β-carboline analogues, the most in vitro active 5-HT1A ligands were found among butylene chain analogues. N

It seems that apart from derivative with dimethylene O N spacer, the introduction of acyl groups which reduced O N the basicity of the N2 nitrogen atom had a positive H CH3 N N N effect on the compound binding ability to 5-HT1A receptors. On the other hand, the investigated THGCs O N N were signiﬁ cantly less active at 5-HT sites, except 2A CH two derivatives. Moreover, those two compounds 3 were at the same time potent 5-HT1A agents, and in- R= -H, -CH , -C H ; R = -H, -2OCH , -Cl terestingly, such dual ligands were previously found 3 6 5 1 3 also in the group of n-butyl-β-carboline derivatives Fig. 9. Structure of series of N-8-arylpiperazinylpropyl of MPP only [37]. derivatives of imidazo[2,1-f]purine-2,4-dione and amide The terminal amide fragment signiﬁ cantly af- derivatives of 6,7-dihydroimidazo[2,1-f]purine-2,4-dione- fects the binding of 1-arylpiperazine derivatives to 7-carboxylicacid. 54 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov

After in vitro investigations the obtained re- it should be stressed that compounds with 2-OCH- or sults showed that the imidazo-derivatives were 3-Cl substituents in the PhP fragment are the most po- potent ligands at 5-HT1A recognition sites. The tent 5-HT1A ligands. On the other hand, introduction of radioligand binding data on the 5-HT1A receptor a branched chain into position 7 of purine-2,6-dione affi nities showed large differences and depend yielded a product with very low 5-HT1A affi nity. An on both, 1-arylpiperazinylpropyl moiety and the analysis of the 5-HT2A receptor binding data of the ob- fragment of imidazo[2,1-f] theophylline. The tained compounds demonstrated their moderate affi n- chemical structure of the terminal imidazo[2,1-f] ity for those receptors. Additionally, the 2-OCH3 and theophylline moiety infl uences the binding param- the 3-Cl derivative displayed a signifi cant 5-HT1A/5- eters. The affi nity of 2- methoxy- and 3-chloro- HT2A selectivity [44]. phenyl-piperazinylpropyl derivatives for 5-HT1A receptor was the lowest for unsubstituted at 7-po- Table 3. Structure-activity relationship of series of 1,3-di- sition of 1,3-dimethyl- (1H,8H)-imidazo[2,1-f] methyl-7-phenylalkyl-8-[3-(4-phenyl-1-piperazi-nyl) purine-2,4-dione derivatives whereat one inac- propylamino]-purine-2,6-dione derivatives tive compound belongs to this group. The most O potent for 5-HT1A receptor was compound with R CH3 phenyl moiety at 7-position of the 1,3-dimethyl- N R1 N H (1H,8H)-imidazo[2,1-f]purine-2,4-dione, and with N (CH2)3N N substituted phenylpiperazine ring. Replacement of O N N phenyl by a methyl moiety in 7-position of the terminal tricyclic fragment afforded the 3-fold less of CH3 5-HT - affi nity for those sites. The amide derivatives of RR1A 6,7-dihydroimidazo[2,1-f]purine-2,4-dione-7-car- 1 affi nity boxylic acid were generally not active at 5-HT1A -CH2-C6H5 H recognition sites. The 5-HT2A receptor affi nity of the target compounds was low, whereas this inac- -CH(CH3)-C6H5 H tive compound displayed higher affi nity for that receptor subtype than for 5-HT1A. The present -(CH2)3-C6H5 H ↑ study indicates that the fi ve-membered heterocyclic ring at 7,8-position of theophylline improved -CH2-C6H5 2-OCH3 5-HT receptor affi nity especially in the case of 1A -(CH ) -C H 2-OCH ↑↑ 2-methoxyphenylpiperazinylpropyl derivatives. 2 3 6 5 3 The obtained results suggested that the LCAPs -(CH ) -C H 3-Cl linked to tricyclic derivatives of the theophylline 2 2 6 5 remain a worthy of future research for obtaining -(CH ) -C H 3-Cl ↑↑↑ new derivatives with potential anxiolytic/antide- 2 3 6 5 pressant activity [45]. ↑-4 times higher affi nity, ↑↑-6 times higher affi nity, ↑↑↑- Grazyna Chlon et al. synthesized a series of new 21 times higher affi nity, than the corresponding analogues 1,3-dimethyl-7-phenylalkyl-8-[3-(4-phenyl-1-piper- with one or two carbon chains. azi-nyl)propylamino]-purine-2,6-dione derivatives and their 5-HT1A and 5-HT2A receptor affi nities were determined (Table 3). LCAPs with a spacer of two to fi ve carbon atoms The results of radioligand binding studies indicate in length usually show optimal 5-HT-receptor affi n- that the increase in aromatic character of the investi- ity. Small structural changes in the length of the alkyl gated compounds, evoked by introduction of pheny- chain can infl uence affi nity, selectivity and type of lalkyl substituents with different alkyl chain lengths in functional activity (agonist vs. antagonist) of the in- position 7 of purine-2,6-dione, resulted in new 5-HT1A vestigated compounds. Maria H. Paluchowska et al. receptor ligands with a higher affi nity for 5-HT1A re- described a series of ω-[4-(2-methoxyphenyl)pipera- ceptor and better 5-HT1A/2A selectivity than those of zin-1-yl]alkyl derivatives with terminal pyrid-2(1H)- their previously investigated analogues. Elongation of one fragments, containing a di- tri- and a tetra-meth- the alkyl chain between the phenyl and the purine-2,6- ylene linking bridge (Fig. 10) that showed diversifi ed dione moieties enhanced 5-HT affi nity. Moreover, 1A 5-HT1A/2A receptor affi nity. Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 55

R1 R2 H3CO ing 4-chloro or 4-fl uoro substituents did not infl u- encethe 5-HT1A receptor affi nity of new amines and ethers (except for the o-OCH containing deriva- R N(CH2)n N N 3 tive) with both ethylene and trimethylene spacers, compared with their previously described unsubsti- O tuted counterparts. On the other hand, for all of the n=2, 3, 4 investigated compounds their affi nities for 5-HT2A receptor sites were very low [48]. Fig. 10. Structure-activity relationship of series of ω-[4- (2-methoxy phenyl)piperazin-1-yl]alkyl derivatives with 2 terminal pyrid-2(1H)-one fragments, containing a di- tri- R and a tetramethylene linking bridge (CH2)n NN X The obtained results showed that the shortening of the aliphatic chain to two methylene groups ex- posed the intrinsic activity of the ligand at 5-HT1A R R receptor sites [46]. Marcin Kolaczkowski et al. synthesized two se- X=NH, O; n=2,3; R2= o-OCH , m-Cl, p-Cl, p-F ries of arylpiperazines with terminal pyrimido[2,1-f] 3 theophylline fragment and trimethylene and tetra- Fig. 12. Structure of compounds, in which was studied the methylene spacer respectively. Their 5-HT1A activi- infl uence of substitution mode of PhP ties were determined (Fig. 11). Maciej Pawłowski et al. synthesized two series O of 1-phenyl piperazinylpropyl derivatives (Fig. 13) O N N structurally related to previously obtained 5-HT1A N R or 5-HT2A ligands, and their binding properties (CH )n N N O N N 2 were determined. Structural modifi cations which involved 1,3-diazepine ring opening and replacement of spiroalkyl n=3,4 moiety by aryl substituent did not improve binding R=H, o-OCH , m-Cl, 3 affi nity and selectivity of the tested compounds. The Fig. 11. Structure of arylpiperazines with terminal results showed, however, that the diazepine ring pyrimido[2,1-f] theophylline fragment and trimethylene or spiroalkyl ring are important for high 5-HT1A or and tetramethylene spacer 5-HT2A binding affi nity and selectivity of these compounds [12]. In the present study was concluded that the Iva Valkova et al. describe the synthesis of three elongation of the aliphatic spacer in model struc- novel 1-benzhydryl-piperazines with xanthine moi- tures from three to four methylene groups improved ety at N4 (Fig. 14), tested for 5-HT1A and 5-HT2A receptor affi nity. 5-HT1A receptor affi nity, especially in the case of o- methoxy phenylpiperazine derivatives, and affected In the present study is established, that compound with no spacer is a very weak binder to both the functional activity in vivo of these new 5-HT1A receptor ligands [47]. 5-HT1A and 5-HT2A receptors. The amide derivative

Maria H. Paluchowska et al. described two series with methylene spacer n = 3 is weak 5-HT1A binder of compounds, in which was studied the inﬂ uence of and moderate 5-HT2A binder. Thus, it is 5 times more substitution mode of PhP (Fig. 12). selective on 5-HT2A than on 5-HT1A. The compound

Almost all 1-(2-methoxyphenyl)piperazine de- with methylene spacer of n = 3 shows weak 5-HT1A rivatives displayed high to moderate affi nity for affi nity and high 5-HT2A affi nity. It is 34 times more selective on 5-HT than on 5-HT receptors and 5-HT1A receptors, except for the ether containing 2A 1A compound. Replacement of the 2-methoxy group in showed the highest affi nity and selectivity to 5-HT2A the arylpiperazine pharmacophore with a 3-chloro receptor known for this class of compounds. substituent was not a benefi cial change in the li- A set of the three new and 31 previously synthe- gand structure. Introduction of electron–withdraw- sized 1-arylpiperazines with xanthine moiety at N4 56 PHARMACIA, vol. 60, No. 1/2013 L. Andonova, M. Georgieva, Al. Zlatkov was compiled and a QSAR study was performed in order to rationalize the further synthesis. It was found N N (CH )n R that the 5-HT1A affi nity depends on the shape of the 2 1 molecules (ovality and number of circuits), the distribution of the electron density in the structures (partial charges at piperazine N1 and xanthine N1) and R1= their charge transfer ability (HOMO energy). The

5-HT afﬁ nity depends on the lipophilicity of the li- O O O CH 2A H3C H3C 3 gands and the distribution of the electron density in N CH3 N CH3 N N H N N the structures (partial charges at piperazine N4 and N N N N xanthine O6). N O N O O N CH 3 CH3 CH3 O (CH2)3 n= 0(comp.1); 3(comp.2-3) H3C N N N Fig. 14. Structure of three novel 1-benzhydryl-piperazines (CH ) N N 2 3 with xanthine moiety at N4 O N N

CH3 1-Arylpiperazines are well known 5-HT recep- O tor ligands with 5-HT and/or 5-HT affi nity. R 1A 2A The inclusion of a complex heterocyclic fragment H3C N N H through a polymethylene spacer at piperazine posi- N (CH ) N N 2 3 tion N4 often leads to more potent ligands in both O N N 5-HT1A and 5-HT2A affi nities. Xanthines are well CH3 known mild CNS agents acting as antagonists of adenosine receptors. R=CH3, n-C4H9 In summary, the present study describes the syn- O (H2C)4 thesis and 5-HT1A/2A receptor affi nity of novel 1-ar-

ylpiperazine derivatives with 5-HT2A selectivity. The HN N (CH2)3N N 2D-QSAR study reveals several structural features responsible for the afﬁ nity and selectivity of 5-HT O ligands with benzhydryl substituent at N1 and xan- O thine moiety at N4. The results from the QSAR study (CH2)nCOOC2H5 H C 3 N and the analysis of 5-HT2A pharmacophore elements N H N (CH2)3N N directed to the next rational synthesis of new selective ligands [49]. O N N

CH3 Conclusion n=1, 3 As described in this survey, the 5-HT system

R is believed to play an important role in the patho- genesis and treatment of mood disorders. Today, the antidepressants form the 3rd largest therapeutic area, with a current annual growth of 20%. Two- thirds of the prescribed antidepressants are recep- O O N tor antagonists and reuptake inhibitors. Today’s’ antidepressants suffer from poor response, late N (CH2)3N clinical onset-of-action and side effects - nausea and sexual dysfunction - that seriously affect pa- xHCl R=H, 3’-Br, 3’-Cl, 4’-F, 4’-Br tience compliance. The search for new molecules from the arylpiper- Fig. 13. Structure of series of 1-phenylpiperazinylpropyl azine group opens the possibility to obtaine products derivatives with structural modifi cations which involved with reduced side effects. We consider, that the com- 1,3-diazepine ring opening and replacement of spiroalkyl bination of active principles of xanthine and arylpip- moiety by aryl substituent Arylpiperazine derivatives – new agents affecting mood disorders PHARMACIA, vol. 60, No. 1/2013 57 erazine moieties will increase the opportunities for 12. P a w ł owski M, Chłoń G, Obniska J, Zejc A, development of more potent agents, as seen from the Charakchieva-Minol S, Mokrosz MJ. Synthe- data, which also includes some results of our own, sis, 5-HT1A and 5-HT2A receptor affi nity of new discussed in the review. 1-phenylpiperazinyl propyl derivatives of purine-2, 6 - and pyrrolidine-2,5-diones. Il Farmaco Reference 2000; 55: 461–468 1. Goodman LS, Hardman JG, Limbird LE, Gil- 13. Borsini F, Evans K, Jason K, Rohde F, Alex- man AG. Goodman&Gilman’s the pharmacolog- ander B, Pollentier S. Pharmacology of Fliban- ical basis of therapeutics. 10th ed. McGraw-Hill, serin. CNS Drug Rev 2002; 8: 117–142. New York, 2001. 14. Invernizzi RW, Sacchetti G, Parini S, Ac- 2. Kandel ER, Schwartz JH, Jessel TM. Prin- concia S, Samanin R. Flibanserin, a potential ciples of Neural Science. 4th ed. McGraw-Hill, antidepressant drug, lowers 5-HT and raises do- New York, 2000. pamine and noradrenaline in the rat prefrontal 3. Fletcher A. Nerve cell function and synaptic cortex dialysate: Role of 5-HT1A receptors. Br J mechanisms. Anaesthesia & intensive care medi- Pharmacol 2003; 139: 1281–1288. cine 2008; 9(6): 270-274. 15. Jolly E, Clayton A, Thorp J, Lewis-D’Agostini 4. Palmer AM. The role of the blood – CNS G. Design of Phase III pivotal trials of fl ibanser- barrier in CNS disorders and their treatment. in in female Hypoactive Sexual Desire Disorder Neurobiology of Disease 2012; 37: 3–12. (HSDD). Sexologies 2008; 17: 133–134. 5. Pryce CR, Azzinnari D, Spinelli S, Seifritz 16. Cusack B, Nelson A, Richelson E. Binding of E, Tegethoff M, Meinlschmidt G. Helplessness: antidepressants to human brain receptors: focus A systematic translational review of theory and on newer generation compounds”. Psychophar- evidence for its relevance to understanding and macology 1994; 114(4): 559–565. treating depression. Pharmacology & Therapeu- 17. Sanchez C, Hyttel J. Comparison of the ef- tics 2011; 132: 242–267. fects of antidepressants and their metabolites 6. Britta H, Heinz B. Depression and antidepres- on reuptake of biogenic amines and on receptor sants: Insights from knockout of dopamine, sero- binding. Cellular and Molecular Neurobiolgy tonin or noradrenaline re-uptake transporters. Phar- 1999; 19(4): 467-489. macology & Therapeutics 2011; 129: 352–368. 18. Marek GM, McDougle CJ, Price LH, Seiden 7. Alex KD, Pehek EA. Pharmacologic mecha- LS. A comparison of trazodone and fl uoxetine: nisms of serotonergic regulation of dopamine implications for a serotonergic mechanis of an- neurotransmission. Pharmacology & Therapeu- tidepressant action, Psychopharmacology 1992; tics 2007; 113: 296–320. 109(1-2): 2-11. 8. Hoyer D, Clarke DE, Fozard JR, Hartig 19. Stahl SM, Mechanism of Action of Trazo- PR, Martin GR, Mylecharane EJ, Saxena done: a Multifunctional Drug. CNS Spectr 2009; PR, Humphrey PP. International Union of 14(10): 536-546. Pharmacology classifi cation of receptors for 20. T ekes K, Tothfalusi L, Malomvolgyi B, Her- 5-hydroxytryptamine (Serotonin). Pharmacol man F, Magyar K. Studies on the biochemical Rev 1994; 46(2): 157–203. mode of action of EGYT-475, a new antidepres- 9. Raymond JR, Mukhin YV, Gelasco A, Turner sant. Polish Journal of Pharmacology and Phar- J, Collinsworth G, Gettys TW, Grewal JS, Gar- macy 1987; 39(2):203-11 novskaya MN. Multiplicity of mechanisms of 21. Broekkamp CLE, Leysen D, Peters BWMM, serotonin receptor signal transduction. Pharma- Pinder RM. Prospects for improved depressants. col Ther 2001; 92 (2-3): 179–212. J Med Chem1995; 38: 4615–4633. 10. Walstab J, Rappold G, Niesler B. 5-HT 3 re- 22. Obniska J, Pawłowski M, Kołaczkowski ceptors: Role in disease and target of drugs. Phar- M, Czopek A, Beata Duszyńska, Kłodzińska macology & Therapeutics 2010; 128: 146–169. A, Tatarczyńska E,Chojnacka-Wójcik E. Syn-

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 Correspondence: Lily Andonova Faculty of pharmacy, Medical University, Soﬁ a 2 “Dunav” str., 1000 Soﬁ a, Bulgaria Phone: +359 2 9236 543; E-mail address: [email protected]