Design and Synthesis of New Benzimidazole-Arylpiperazine Derivatives Acting as Mixed 5-HT 1A /5-HT 3 Ligands Marı ´ aL.Lo´pez-Rodrı ´ guez, a, * Bellinda Benhamu´, a M a Jose´ Morcillo, b Ignacio Tejada, a David Avila, a Isabel Marco, a Lucio Schiapparelli, c Diana Frechilla c and Joaquı ´ nDelRı ´ o c a Departamento de Quı´mica Orga ´nica I, Facultad de Ciencias Quı´micas, Universidad Complutense, E-28040 Madrid, Spain b Seccio ´n de Quı´mica, Facultad de Ciencias, Universidad Nacional de Educacio ´n a Distancia, E-28040 Madrid, Spain c Departamento de Farmacologı´a, Facultad de Medicina, Universidad de Navarra, E-31008 Pamplona, Spain Received 16 May 2003; revised 24 June 2003; accepted 1 July 2003 Abstract—Aseriesofnewbenzimidazole-arylpiperazinederivatives III weredesigned,synthesizedandevaluatedforbindingaffinity at serotoninergic 5-HT 1A and 5-HT 3 receptors. Compound IIIc was identified as a novel mixed 5-HT 1A /5-HT 3 ligand with high affinity for both serotonin receptors and excellent selectivity over a 1 -adrenergic and dopamine D 2 receptors. This compound was characterized as a partial agonist at 5-HT 1A Rs and a 5-HT 3 R antagonist, and was effective in preventing the cognitive deficits inducedbymuscarinicreceptorblockadeinapassiveavoidancelearningtest. # 2003ElsevierLtd.Allrightsreserved. Introduction Thediscoveryofnewligandswithaffinityforthefamily of serotonin receptors (5-HTRs) is an area of active research in Medicinal Chemistry due to their involve- mentinnumerousphysiologicalandpathophysiological processes. 1 4 At present seven classes of serotonin receptors (5-HT 1 7 ) including 14 subtypes have been found, 5,6 andmostofthembelongtothesuperfamilyof Gprotein-coupledreceptors(GPCRs);onlythe5-HT 3 R is a ligand-gated cation channel receptor. 7 Among 5- HTRs, the 5-HT 1A is involved in psychiatric dis- orders 8 11 suchasanxiety,depressionandmemoryloss. On the other hand, 5-HT 3 R antagonists are of special interest not only because of their wide clinical use as antiemetic drugs in cancer patients, 12,13 but also due to theirpromisingtherapeuticpotentialinthetreatmentof CNS disorders, 14 16 such as anxiety, drug abuse and withdrawal, and cognitive dysfuntion. In light of the potential utility in anxiety and cognitive disorders of 5- HT 1A and 5-HT 3 receptor ligands, it would be of inter- est, in principle, the development of compounds with affinityatboth5-HTRsubtypes. In the course of a program aimed at the discovery of new 5-HT 1A and 5-HT 3 agents, we have synthesized a series of arylpiperazines 17 22 I as potent 5-HT 1A R ligands and a class of azabicyclic benzimidazole deriva- tives II which exhibited high affinity for the 5-HT 3 R 23 (Fig. 1). In the present work, we have designed a series of new mixed benzimidazole-arylpiperazines of general structure III in which we have incorporated the struc- tural elements of 5-HT 1A and 5-HT 3 pharmacophores (Fig. 1). Among them, compound IIIc has shown high affinity for both 5-HT 1A and 5-HT 3 receptors, and has beencharacterizedasapartialagonistat5-HT 1A Rsand a 5-HT 3 R antagonist with a potential interest in the treatment of cognitive dysfunction. Chemistry The general procedure for the preparation of target compounds III is shown in Scheme 1. Starting ben- zimidazole carboxylic acids 1a–k were coupled with (  )-3-aminoquinuclidine to afford the desired amides IIIa–k. 2-[(4-arylpiperazin-1-yl)methyl]benzimidazole- 4-carboxylic acids 1a–k were obtained by reaction of 2-(chloromethyl)benzimidazole-4-carboxylic acid 3 with the corresponding arylpiperazine. The acid 3 was prepared by condensation of 2,3-diaminobenzoic 0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0960-894X(03)00706-6 Bioorganic & Medicinal Chemistry Letters 13 (2003) 3177–3180 *Corresponding author. Tel.:+34-913-944-239; fax:+34-913-944-103; e-mail: mluzlr@quim.ucm.es