Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.

摘要: A series of trans-1-piperazino-3-phenylindans were synthesized with the goal replacing their established neuroleptic profile that peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds an unsubstituted or fluoro-substituted 6-position in indan ring, and which had a five- six-membered heterocyclic ring attached by ethylene chain to piperazine satisfied this objective. Some compounds potent antihypertensive activity conscious, spontaneously hypertensive rats (SHR). In pithed they antagonized pressor effect induced 5-HT doses 100-1000 times lower than needed antagonize phenylephrine. The was stereoselective associated enantiomers 1R,3S absolute configuration. 1S,3R inhibited uptake dopamine norepinephrine vitro. compound best (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological resembled standard ketanserin. There close structural correspondence between ketanserin irindalone conformation we recently identified as D-2 receptor-relevant configuration its "parent" tefludazine. This suggests dopaminergic (D-2) serotonergic pharmacophores are structurally closely related.