Struture-activity relationship studies of CNS agents .26. 4-[2-(Cycloalkanecarboxamido)ethyl]-1-(2-methoxyphenyl)-piperazines: High-affinity 5-HT1A agonists

Cycloalkanecarboxamido)ethyl]-1-(2-methoxyphenyl)piperazines 8a-c, 8e, and 8h were obtained by acylation of 4-(2-aminoethyl)-1-(2-methoxyphenyl)piperazine, and their 5-HT1A, 5-HT2A and alpha(1) receptor affinities were determined. It was found that the terminal cycloalkane moiety strongly stabilizes both the 5-HT1A and 5-HT2A receptor-ligand complexes. It was demonstrated that the most active 5-HT1A ligands 8e and 8h (K-i = 2.1 and 0.21 nM, respectively) behaved as potent agonists of these receptors, i.e. both derivatives mimicked 8-OH-DPAT in the lower lip retraction (LLR) model and the effect was susceptible to blockade by reasonable doses of the selective 5-HT1A receptor antagonist (S)-WAY-100135.