STRUCTURE AFFINITY RELATIONSHIP STUDIES ON 5-HT1A RECEPTOR LIGANDS .1. HETEROBICYCLIC PHENYLPIPERAZINES WITH N4-ALKYL SUBSTITUENTS

Structure-affinity relationship (SAR) studies for 5-HT1A receptor site are presented for two series of heterobicyclic phenylpiperazines with N4-alkyl substituents: 4-alkyl derivatives of 1-(2,3-dihydro-1,4-benz odioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl we re synthesized and evaluated for their ability to displace [H-3]-2-(di -n-propylamino)-8-hydroxytetralin from its specific binding sites in r at frontal cortex homogenates. All compounds displayed a nanomolar aff inity for the 5-HT1A receptor. In both series the N-ethyl and N-n-prop yl substituted derivatives have similar affinities, being slightly but statistically significantly less active than the N-methyl-substituted derivatives. Elongation of the hydrocarbon chain increases the affini ty for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (K(i) = 0.50 nM) and 39 (K(i) = 0.54 nM). Assuming that the arylpiperazine derivatives at the 5-HT1A binding site are in the ionic state, ionization constants were determined in order to evaluate the use of the local inhibition const ant, K(i)+, as a more convenient parameter to study the structure-affi nity relationships. However, the K(i)+ could not account for the speci fic N4-substituent effects found.