molecules Article Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties Vittorio Canale 1 , Magdalena Kota ´nska 2 , Anna Dziubina 2, Matylda Stefaniak 1 , Agata Siwek 3, Gabriela Starowicz 3, Krzysztof Marciniec 4 , Patryk Kasza 1, Grzegorz Satała 5, Beata Duszy ´nska 5 , Xavier Bantreil 6 , Frédéric Lamaty 6, Marek Bednarski 2, Jacek Sapa 2 and Paweł Zajdel 1,* 1 Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland; [email protected] (V.C.); [email protected] (M.S.); [email protected] (P.K.) 2 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland; [email protected] (M.K.); [email protected] (A.D.); [email protected] (M.B.); [email protected] (J.S.) 3 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland; [email protected] (A.S.); [email protected] (G.S.) 4 Department of Organic Chemistry, Medical University of Silesia, 41-200 Sosnowiec, Poland; [email protected] 5 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, Poland; [email protected] (G.S.); [email protected] (B.D.) Citation: Canale, V.; Kota´nska,M.; 6 IBMM, Université de Montpellier, CNRS, ENSCM, 34095 Montpellier, France; Dziubina, A.; Stefaniak, M.; Siwek, A.; [email protected] (X.B.); [email protected] (F.L.) Starowicz, G.; Marciniec, K.; Kasza, P.; * Correspondence: [email protected]; Tel.: +48-12-620-5500 Satała, G.; Duszy´nska,B.; et al. Design, Sustainable Synthesis and Abstract: The complex pathophysiology of depression, together with the limits of currently available Biological Evaluation of a Novel Dual antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Nu- α2A/5-HT7 Receptor Antagonist merous findings suggest that pharmacological blockade of α -adrenoceptor might be beneficial for with Antidepressant-Like Properties. 2 Molecules 2021, 26, 3828. the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in https://doi.org/10.3390/ certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have molecules26133828 been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of Academic Editors: Marcello Leopoldo arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. and Enza Lacivita Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 Received: 25 May 2021 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and Accepted: 18 June 2021 selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice Published: 23 June 2021 in the forced swim test, displaying similar potency to the reference drug mirtazapine. Publisher’s Note: MDPI stays neutral Keywords: α2 adrenoceptor antagonist; 5-HT7 receptor antagonist; medicinal mechanochemistry; with regard to jurisdictional claims in depression; forced swim test published maps and institutional affil- iations. 1. Introduction Depressive disorder is a common and disabling illness characterized by the presence Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. of behavioral and emotional symptoms (i.e., sleep disturbances, low self-esteem, sadness as This article is an open access article well as suicidal ideation) [1]. Although different pharmacotherapeutic options are available distributed under the terms and (e.g., selective serotonin reuptake inhibitors SSRIs–; serotonin/noradrenaline reuptake conditions of the Creative Commons inhibitors SNRIs; monoamine receptors modulators), the treatment of depressive disorders Attribution (CC BY) license (https:// is still limited. Currently available antidepressants display a delay of therapeutic action, creativecommons.org/licenses/by/ which lasts up to a few weeks in some patients after numerous antidepressant drugs, and 4.0/). numerous unacceptable side effects [2]. Molecules 2021, 26, 3828. https://doi.org/10.3390/molecules26133828 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 20 Molecules 2021, 26, 3828 sive disorders is still limited. Currently available antidepressants display a delay of2 ther- of 19 apeutic action, which lasts up to a few weeks in some patients after numerous antidepres- sant drugs, and numerous unacceptable side effects [2]. The α2-adrenoceptor (α2-AR) is a member of class A of G-protein coupled receptors The α2-adrenoceptor (α2-AR) is a member of class A of G-protein coupled receptors (GPCRs)(GPCRs) canonicallycanonically associated associated with with heterotrimeric heterotrimeric Gi/o Gi/o subtypes.subtypes. ItsIts activationactivation leadsleads toto inhibitioninhibition ofof adenylyladenylyl cyclase cyclase and and voltage-gated voltage-gated calcium calcium channels channels [3]. [3] Among. Among the the identified identi- fied α2-ARs, α2A-AR subtype is the predominant isoform (90% of all α2-AR) and represents α2-ARs, α2A-AR subtype is the predominant isoform (90% of all α2-AR) and represents the primarythe primary modulators modulators of monoaminergic of monoaminergic neurotransmission neurotransmission in CNS in CNS [4]. In[4] particular,. In particular the, the high expression of α2A-AR in the hippocampus and cortico-limbic structures together high expression of α2A-AR in the hippocampus and cortico-limbic structures together with itswith involvement its involvement in serotonin in serotonin release [ 5release,6], asserts [5,6] its, pivotalasserts roleits pivotal in cognition, role memory,in cognition, and moodmemory disorders, and mood [7]. disorders [7]. The 5-HT5-HT77 receptor (5-HT(5-HT77R) represents the latest addition to a subfamily of serotonin GPCRs [[8]8].. AllAll isolatedisolated 5-HT5-HT77R isoforms are positivelypositively coupledcoupled toto adenylateadenylate cyclasecyclase viavia activationactivation of the GGαsαs subunit with consequent increasingincreasing of intracellular cAMP level levelss [9] [9].. TheThe distributiondistribution ofof 5-HT5-HT77R in specificspecific CNS regions (i.e.,(i.e., thethe hippocampushippocampus andand prefrontalprefrontal cortex) suggests itsits implicationsimplications inin thethe controlcontrol ofof rapidrapid eyeeye movementmovement sleep,sleep, learning,learning, andand memory asas wellwell asas in in pathological pathological processes processes such such as as affective affective disorders, disorders, neurodegenerative neurodegenera- diseases,tive diseases and, cognitiveand cognitive decline decline [10,11 [10,11]]. A back-dropback-drop of evidenceevidence has demonstrateddemonstrated the potential of genetic and pharmaco- logicallogical blockadeblockade ofof αα22--ARAR and 5 5-HT-HT7RR in in several several preclinical preclinical models of depression [12 [12–15]15].. TheseThese findingsfindings areare furtherfurther supportedsupported byby thethe factfact thatthat augmentationaugmentation ofof thethe SSRIsSSRIs andand NRSIsNRSIs withwith αα22--ARAR or 5-HT5-HT7R antagonists increases their efficiency efficiency of monoamine reuptake in- hibitors [[1616–1818]].. Of note,note, thethe antidepressantantidepressant effectseffects ofof mianserinmianserin andand mirtazapine,mirtazapine, whichwhich display high-to-moderatehigh-to-moderate affinityaffinity for for several several monoaminergic monoaminergic receptors receptors and and transporters, transporters, is mainlyis mainly attributed attributed to to their their antagonism antagonism at presynapticat presynapticα2A α-AR2A-AR [19 [19,20],20]. Recent studiesstudies in in a a group group of of arylsulfonamide arylsulfonamide derivatives derivatives of aryloxyalkylpiperidine of aryloxyalkylpiperidine [21] identified[21] identified compound compound I as a potentI as a potent 5-HT7 R5- ligandHT7R ligand with affinity with affinity for α2-AR for in α a2-AR submicromolar in a submi- rangecromolar (Figure range1). (Figure Further 1). replacement Further replacement of the flexible of the flexible isopropoxy isopropoxy moiety moiety with the with rigid the 2,2-dimethyl-2,3-dihydrofuranerigid 2,2-dimethyl-2,3-dihydrofurane moiety moiety increased increased the affinity the affinity for α for2-AR, α2-AR, providing providing the α moderatethe moderate2-AR α2- ligandAR ligand6 (Figure 6 (Figure1). At 1). the At same the same time, time, this modification this modification maintained maintained high affinityhigh affinity for 5-HT for 75R.-HT These7R. These findings findings prompted prompted us to designus to design novel dualnovel acting dual compoundsacting com- α whichpounds behave which asbehave2-AR as and α2-AR 5-HT and7R antagonists.5-HT7R antagonists. Figure 1. Design strategy for the arylsulfonamide derivatives ofof (aryloxy)ethyl(aryloxy)ethyl piperidinespiperidines 66––1919.. Here,Here, we present present a a medicinal medicinal mechanochemistry mechanochemistry approach approach to tothe the generation generation of a of fo- a focusedcused library library of of arylsulfonamides arylsulfonamides