New 4-[omega-(diarylmethylamino)alkyl]- and 4-[omega-(diarylmethoxy)alkyl]-1-arylpiperazines as selective 5-HT1A/5-HT2A receptor ligands with differentiated in vivo activity.

Two series of novel 4-ethyl- or 4-propyl-1-arylpiperazines (5-12) with the 4,4'-disubstituted diphenylmethylamino (series a) or the diphenylmethoxy (series b) terminal fragment were synthesized and evaluated for their binding affinity at 5-HT1A and 5-HT2A receptors. The influence of the introduction of 4-methyl, 4-chloro or 4-fluoro substituents at both phenyl rings of that terminal moiety on in vitro and in vivo 5-HT1A receptor activity of those modified compounds was discussed. Compounds 5a, 6a, 9a-12a, 5b, 6b, 9b, 11b and 12b displayed high to fairly high affinity for 5-HT1A receptors (Ki = 2.4-72 nM). Compounds of both series showed low or very low 5-HT2A receptor affinity (Ki = 155-5400 nM). Amines 5a, 6a, 11a, and their ether analogs 5b, 6b and 11b, also possessed high or moderate alpha(1)-adrenoceptor affinity (K(i) = 6-104 nM). The functional activity of compounds 5a, 6a, 9a-12a, 5b, 8b, 9b, 11b and 12b was tested in vivo in the commonly used animal models. The majority of those ligands behaved like 5-HT1A receptor antagonists, their influence on the pre- and/or postsynaptic sites being diverse, though. They exhibited characteristics of partial agonists of postsynaptic 5-HT1A receptors (11a), of weak antagonists of pre- and postsynaptic sites (12a, 9b), of antagonists of presynaptic (5a) or of antagonists of postsynaptic 5-HT(1A) receptors (9a, 10a, 5b, 8b, 11b and 12b) while, 6a was devoid of functional activity at those receptors. The above findings indicate that introduction of 4-methyl, 4-chloro or 4-fluoro substituents to the diphenylmethyl part of the 1-(2-methoxyphenyl)piperazines tested in vivo may modify their 5-HT1A receptor functional activity.