Synthesis and D(2)-like binding affinity of new derivatives of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide and related 4H-[1]benzothiopyrano[4,3-b]pyrrole and 5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide analogues.
Various new derivatives and structural analogues of N-(1-ethyl-2-pyrrolidinylmethyl)-4,5-dihydro-1H-benzo[g]indole-3-carboxamide (2a), a representative term of a series of 2-aminomethylpyrrolidinyl derived 4,5-dihydrobenzo[g]indolcarboxamides with good D(2)-like affinity, were synthesized and evaluated for their ability to bind to dopamine D(2)-like receptors in vitro. The structural contribution to D(2)-like receptor binding of the 4,5-dihydrobenzo[g]indole portion of the molecule was examined. From these studies, compound 2k, 2-chloro-N-(1-ethyl-2-pyrrolidinylmethyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[b]pyrrole-3-carboxamide, was found to possess a potent affinity for D(2)-like receptors. Behavioural tests in rats have shown that this compound reduces the hyperactivity induced by amphetamine, a property shared by all antipsychotic drugs, at a dose which failed to induce catalepsy, an effect which is predictive of extrapyramidal side effects in humans. The other compounds demonstrated moderate (2c, 2h, and 2j) or no affinity for D(2)-like receptors.
Pinna
Gérard A
GA
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy. pinger@ssmain.uniss.it
Pirisi
Maria A
MA
Chelucci
Giorgio
G
Mussinu
Jean M
JM
Murineddu
Gabriele
G
Loriga
Giovanni
G
D'Aquila
Paolo S
PS
Serra
Gino
G
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000661:Amphetamine; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles; D011485:Protein Binding; D011595:Psychomotor Agitation / Q000188:drug therapy; D011758:Pyrroles; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000577:Amides; D014150:Antipsychotic Agents; D007211:Indoles; D011758:Pyrroles; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000661:Amphetamine