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Synthesis and in Vitro Pharmacological Evaluation of a New Series of 5-HT1A 5-HT2A and 5-HT2C Receptor Ligands Containing a Norbornene Nucleus

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Synthesis and in Vitro Pharmacological Evaluation of a New Series of 5-HT1A 5-HT2A and 5-HT2C Receptor Ligands Containing a Norbornene Nucleus ORIGINAL ARTICLES Dipartimento di Chimica Farmaceutica e Tossicologica1, Universita` degli Studi di Napoli “Federico II”, Napoli, Dipartimento di Farmacologia “G. Segre” 2, Universita` di Siena, Italy Synthesis and in vitro pharmacological evaluation of a new series of 5-HT1A 5-HT2A and 5-HT2C receptor ligands containing a norbornene nucleus F. Fiorino1, B. Severino1, F. De Angelis1, E. Perissutti1, E. Magli1, F. Frecentese1, A. Esposito1, P. Massarelli2, C. Nencini2, B. Viti2, V. Santagada1, G. Caliendo1 Received April 4, 2009, accepted May 7, 2009 Prof. Giuseppe Caliendo, Dipartimento di Chimica Farmaceutica e Tossicologica Universita` degli Studi di Napoli “Federico II”, Via D. Montesano, 49, 80131 Napoli, Italy [email protected] Pharmazie 64: 555–564 (2009) doi: 10.1691/ph.2009.9593 A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (a1 and a2) receptors. The combination of structural elements (heterocyclic nucleus, oxyal- kyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin recep- tors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A,5- HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1,D2, a1 and a2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5- dione (Ki ¼ 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5- HT2A/5-HT2C activity with affinity values in nanomolar range. 1. Introduction HT2C receptor is considered to be an attractive target for Evidence suggests that serotonin (5-hydroxytryptamine, 5- the design of novel drugs for treatment of CNS-related HT), is an important neurotransmitter in the central and diseases such as obesity, obsessive compulsive disorder, peripheral nervous systems (CNS and PNS, respectively), and sexual dysfunction, even if few 5-HT2C selective ago- implicated in numerous physiological and pathophysiolo- nists are known so far (Shimada et al. 2008). gical processes (Baumgarten et al. 1987; Martin et al. 5-HT1AR, 5-HT2AR and 5-HT2CR are G protein coupled 1998; Barnes et al. 1999; Hoyer et al. 2002; Shimada et al. receptors (GPCRs) (Sleight et al. 1991; Bikker et al. 1998) 2008). In fact, serotonin receptors (5-HTRs) may be in- that show an amino acid composition similar to adrenergic volved in impulsivity and alcoholism (De Vry et al. 1995; and dopaminergic receptors. In particular, the 5-HT1AR File et al. 1996), in the different phases of sleep (Neckel- transmembrane amino acid sequence presents 45% homol- mann et al. 1996), sexual behavior, appetite control, ther- ogy with the respective part of the a1-adrenergic receptor moregulation, cardiovascular function (Sleight et al. 1991; (Trump-Kallmeyer et al. 1992). Saxena et al. 1995) and recently has been found to show Several classes of agents are already known for their high growth-promoting activity and to be functionally related to affinity toward these receptors and, from a chemical point oncogenes (Dizeyi et al. 2004). In particular, the 5-HT1A of view, they can be subdivided into different classes receptor belongs to the superfamily of G-protein-coupled (aminotetralines, ergolines, arylpiperazines, indolylalkyl- receptors and negatively coupled to adenylyl cyclase amines, aporphines, arylalkylpiperidines, indoles and aryl- found in high concentration in the limbic system, where it oxyalkylamines). One of the most studied group is that of is thought to play a role in emotional processes and repre- long-chain arylpiperazine (LCAPs), (Lopez-Rodriguez sents a major target for research and drug development et al. 2002; Pessoa-Mahana et al. 2003) that have provided due to its implication in the pathophysiology and treat- interesting drugs acting on the CNS (buspirone, ziprasi- ment of major neuropsychiatric disorders, including de- done, aripiprazol) and compounds with a potential thera- pression, schizophrenia and anxiety. Moreover, the 5-HT2A peutical profile (adatanserin, mazapertine, flesinoxan, leco- receptor is known to play a key role in the action of psy- zotan, bifeprunox, tandospirone) which, among others, chedelics as well as being a therapeutic target for the treat- exert their action via 5-HT1A and 5-HT2A receptors. Their ment of schizophrenia (Parker et al. 2008), whereas the 5- diversified receptor binding profiles and intrinsic activities, Pharmazie 64 (2009) 9 555 ORIGINAL ARTICLES Scheme analyzed a new set of derivatives where the piperazine-N- alkyl moiety has been linked to a norbornene fragment O O (Scheme); introducing this heterocyclic nucleus in already reported compounds afforded arylpiperazine derivatives i N OH N O (CH2)n Cl with high affinity and selectivity towards 5-HT1A receptor (Fiorino et al. 2005). The relevance of the norbornene nu- O O (2a) n=2 (1) (3a) n=3 cleus as terminal fragment was already supported by un- ii constrained molecular dynamics simulations that showed a very stable orientation and position of the norbornene O part, emphasizing its favourable properties as anchoring group (Fiorino et al. 2005). In this paper, we describe a N O (CH2)n N N X new series of derivatives in which, this bicyclic nucleus O (2h-u) n=2 has been linked via two or three methylene spacing units (3h-u) n=3 to piperazines substituted in position 4 with aliphatic and/ or aromatic moieties, aiming to further explore the interac- Reagents and conditions: (i) Br(CH2)nCl, NaOH, absolute EtOH, 70 C, tion with 5-HT , 5-HT and 5-HT receptors. In parti- 24 h; (ii) 4-X-substituted-piperazine, K CO ,NaI,CHCN, reflux, 24 h 1A 2A 2C 2 3 3 cular, the choice of aliphatic substituents on the N-4 of depending on either the kind of substituent attached to the the piperazine moiety, that could appear in contrast with N-4 atom of the piperazine moiety or the nature of an the statement that protonable nitrogen and aromatic sys- amide or imide terminal fragment, open the possibility for tem are necessary for binding of aminergic ligand, was discovery of new potent therapeutic agents (Zajdel et al. done in order to obtain a complete structure-affinity and 2007). The influence of each part of the LCAP structures structure-selectivity relationship study. Instead, the role of oxygen atom in the chain linker was already clarified by on the 5-HT1A and 5-HT2A receptor affinity, intrinsic ac- tivity, and selectivity has been the subject of many SAR molecular modelling studies showing that the oxygen studies, whereas there are few evidences regarding the in- leads to more favourable changes in steric as well as elec- trostatic interaction between the norbornene derivatives teraction of the LCAP structures on the 5-HT2C receptor. In our laboratories, there has been an ongoing effort to and the receptor (Fiorino et al. 2005). Moreover, the multi- receptor profiles of promising derivatives were also evalu- develop new 5-HT1A agents (Caliendo et al. 1993, 1995, 1996, 1999, 2000, 2001, 2002; Fiorino et al. 2005, 2008) ated in terms of binding affinities for dopaminergic (D1, with high affinity and selectivity over other serotoninergic, D2) and adrenergic (a1, a2) receptors. dopaminergic and adrenergic receptors. In continuation of our research program, the aim of this work was also to 2. Investigations, results and discussion better clarify the structural features needed in order to make the LCAPs able for the interaction with 5-HT2A and The general strategy for the synthesis of the target com- 5-HT2C receptors. Based on this consideration we have pounds (Table 1) is summarized in Scheme 1. The general Table 1: Affinities of compounds 2h–u and 3h–u for 5-HT1A, 5-HT2A and 5-HT2C receptors O N O (CH2)n N N X O Compd. Receptor affinity Ki Æ SD (nM) X n 5-HT1A 5-HT2A 5-HT2C [3H]8OH-DPAT [3H]Ketanserin [3H]Mesulergine 2h 2 no affinity >104 >104 2i 2 no affinity >104 1590 Æ 524 OCH3 2l 2 no affinity >104 >104 OCH2CH3 2m 2 no affinity 25.3 Æ 2.6 6.79 Æ 0.08 OCH3 2n OCH2CH3 2 5.67 Æ 0.3 381 Æ 16 10.9 Æ 4.9 2o NC 2 4.82 Æ 0.05 83.7 Æ 1.9 6.61 Æ 0.26 556 Pharmazie 64 (2009) 9 ORIGINAL ARTICLES Table 1: Continued Compd. Receptor affinity Ki Æ SD (nM) X n 5-HT1A 5-HT2A 5-HT2C [3H]8OH-DPAT [3H]Ketanserin [3H]Mesulergine 2p H3C CH3 2 15.1 Æ 0.8 14.8 Æ 1.2 17.4 Æ 1.0 2q Cl 2 no affinity 153 Æ 70 1.13Æ 0.16 Cl 2r O 2 no affinity no affinity no affinity O 2s O 2 no affinity 3880 Æ 172 145 Æ 48 O 2t 2 no affinity >104 no affinity Cl 2u F 2 10.3 Æ 0.6 344 Æ 57 10.2 Æ 1.2 F 3h 3 no affinity >104 19.4 Æ 0.8 3i 3 no affinity no affinity no affinity OCH3 3l 3 no affinity >104 11.0 Æ 5.7 OCH2CH3 3m 3 no affinity 71.4 Æ 1.0 4.56 Æ 0.37 OCH3 4 3n OCH2CH3 3 >10 397 Æ 24 5.02 Æ 0.22 3o NC 3 >104 18.8 Æ 1.0 no affinity 3p H3C CH3 3 no affinity 7.48 Æ 0.18 5.16 Æ 0.12 3q Cl 3 >104 13.4 Æ 1.4 no affinity Cl Pharmazie 64 (2009) 9 557 ORIGINAL ARTICLES Table 1: Continued Compd.
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