Novel sulfonamides having dual dopamine D2 and D3 receptor affinity show in vivo antipsychotic efficacy with beneficial cognitive and EPS profile E ´ va A ´ gai-Csongor, * Katalin No ´gra ´di, Ja ´nos Galambos, Istva ´n Va ´go ´ , Attila Bielik, Ildiko ´ Magdo ´, Gyo ¨ rgyi Igna ´cz-Szendrei, Gyo ¨rgy Miklo ´s Keser} u, Istva ´n Greiner, Istva ´n Laszlovszky, E ´ va Schmidt, Be ´la Kiss, Katalin Sa ´ghy, Judit Laszy, Istva ´n Gyertya ´n, Ma ´ria Za ´jer-Bala ´zs, Larisza Ge ´mesi and Gyo ¨rgy Doma ´ny Gedeon Richter Ltd, Budapest, 10. PO Box 27, H-1475, Hungary Received 14 June 2007; revised 7 August 2007; accepted 8 August 2007 Available online 15 August 2007 Abstract—A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most inter- esting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile. Ó 2007 Elsevier Ltd. All rights reserved. An increasing body of clinical evidence supports the no- tion that multiple ligands may be more efficacious than strictly selective agents, particularly in the treatment of CNS disorders. 1 We decided to utilize this approach in our antipsychotic research. Our quest was based on three interrelated hypotheses: (1) that dopamine D2 antago- nism is required for antipsychotic activity; (2) that dopa- mine D3 antagonism may carry favourable effects such as cognitive enhancement and lack of catalepsy; and (3) in order to achieve a simultaneous in vivo manifestation of D2 and D3 antagonism compounds should have a higher affinity to D3 than to D2 receptors. N H O N N CN SB-277011 rD3-Ki: 8.25 nM; rD2-Ki: 4667 nM; r%F: 63 Surveying the literature for drug-like and potent dopa- mine D3 receptor ligands we identified SB-277011 2 as a promising starting point and an analogue (1) prepared by us was subsequently chosen as a lead compound (affinities to rat dopamine D3 and D2 receptors as well as the rat bioavailability were measured in our laborato- ries). 3–5 N H S N CN Cl O O 1 rD3-Ki: 1.68 nM; rD2-Ki: 1166 nM; r%F: 80 After having prepared a few dozen analogues by tra- ditional solution-phase synthesis (as depicted in Scheme 1) 32 representatives were evaluated in a 3D-QSAR study using CoMFA based on their affini- ties to D3 receptors (see Supporting Information). The underlying principle for the selection was that the affinity values should cover as wide a range as possible. All computations were performed using Syb- yl 6.8 molecular modeling software (Tripos Inc.). 6 The 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.08.015 Keywords: Arylsulfonamides; Dopamine D3 and D2 ligands; Antipsy- chotic; Cognition enhancer. * Corresponding author. Tel.: +36 1 431 5112; fax: +36 1 432 6002; e-mail: e.csongor@richter.hu Bioorganic & Medicinal Chemistry Letters 17 (2007) 5340–5344