title: Synthesis and evaluation of heterocyclic carboxamides as potential antipsychotic agents.
abstract: Heterocyclic analogues of 1192U90, 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-butyl) benzamide hydrochloride (1), were prepared and evaluated as potential antipsychotic agents. These analogues were evaluated in vitro for their binding to the dopamine D2, serotonin 5-HT2, and serotonin 5-HT1a receptors and in vivo for their ability to antagonize the apomorphine-induced climbing response in mice. Nine different types of heterocyclic carboxamides were studied in this investigation (i.e., pyridine-, thiophene-, benzothiophene-, quinoline-, 1,2,3,4-tetrahydroquinoline-, 2,3-dihydroindole-, indole-, benzimidazole-, and indazolecarboxamides). Two derivatives exhibited potent in vivo activities comparable to 1: 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl)-2 -pyridinecarboxamide (16) and 3-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)butyl) -2-thiophenecarboxamide (29). Furthermore, these derivatives were found to be much less active in behavioral models predictive of extrapyramidal side effects than in the mouse climbing assay, which predicts antipsychotic activity. Carboxamides 16 and 29 were selected for further evaluation as potential backup compounds to 1.
authors.affiliation: Division of Chemistry, Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Norman
authors.forename: F
authors.initials: F
authors.lastname: Navas
authors.forename: J B
authors.initials: JB
authors.lastname: Thompson
authors.forename: G C
authors.initials: GC
authors.lastname: Rigdon
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D020891:Raclopride; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D012457:Salicylamides / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D006571:Heterocyclic Compounds; D010879:Piperazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012457:Salicylamides; D013844:Thiazoles; C098658:1192U90; D020891:Raclopride; D003024:Clozapine; D018967:Risperidone; D001058:Apomorphine