American Chemical Society
jm0309811_si_001.pdf (48.16 kB)

Pyrrolo[1,3]benzothiazepine-Based Serotonin and Dopamine Receptor Antagonists. Molecular Modeling, Further Structure−Activity Relationship Studies, and Identification of Novel Atypical Antipsychotic Agents

Download (48.16 kB)
journal contribution
posted on 2004-01-01, 00:00 authored by Giuseppe Campiani, Stefania Butini, Caterina Fattorusso, Bruno Catalanotti, Sandra Gemma, Vito Nacci, Elena Morelli, Alfredo Cagnotto, Ilario Mereghetti, Tiziana Mennini, Miriana Carli, Patrizia Minetti, M. Assunta Di Cesare, Domenico Mastroianni, Nazzareno Scafetta, Bruno Galletti, M. Antonietta Stasi, Massimo Castorina, Licia Pacifici, Mario Vertechy, Stefano Di Serio, Orlando Ghirardi, Ornella Tinti, Paolo Carminati
Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo[1,3]benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pKi 5-HT2A/D2 ratio of 1.21 (pKi 5-HT2A = 8.83; pKi D2 = 7.79). The lower D2 receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D2 pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure−activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo[2,1-b][1,3]benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT2A receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D2/5-HT2A receptor ligand with a typical binding profile (9f, pKi 5-HT2A/D2 ratio of 1.01, log Y = 8.43). Then, to reduce D2 receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT2A/D2 receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pKi 5-HT2A/D2 ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED50 >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.