Investigation of mixed D-2/5-HT1A activity of N-heteroarylmethyl-N-phenylpiperazines, N-heteroarylethyl-N-phenylpiperazines and N-heteroarylpropyl-N-phenylpiperazines

Eight novel N-heteroarylalkyl-N-phenylpiperazines have been synthesized, ch emically characterized and evaluated for in vitro binding affinity at the d opamine and serotonin receptors. Synaptosomal membranes of fresh bovine cau date nuclei (D-1 and D-2), the membranes of COS-7 cells (D-4.4) and those p repared from fresh bovine hippocampi (5-HT1A) were used as a source of the corresponding receptor subtypes. [H-3]SCH 23390 (D-1-selective), [H-3]spipe rone (D-2- and D-4.4- selective) and [H-3]-8-OH-DPAT (5-HT1A-selective) ser ved as radioligands. None of the compounds expressed the affinity for the b inding at the D-1 subtype receptor. Compounds 7-9 containing a single methy lene group serving as a bridge between heteroaryl and N-phenylpiperazine pa rt of the molecule were inactive [H-3]spiperone and [H-3]-8-OH-DPAT competi tors. Ligands 15-19 (three methylene groups connecting heteroaryl- and N-ph enylpiperazine part of the molecule) acted as moderate competitors of [H-3] spiperone binding at the D-2 receptor subtype, with the exception of 15 (a thione) which expressed a high binding affinity at the D-2 receptor subtype . Compounds 15-19 behaved as moderate displacers of 8-OH-[H-3]DPAT. Among a ll eight novel ligands only compound 15 expressed a moderate binding affini ty at the D-4.4 receptor subtype.