Structure-affinity relationship studies on 5-HT1A receptor ligands. 1. Heterobicyclic phenylpiperazines with N4-alkyl substituents

• Published in: Journal of medicinal chemistry Vol. 36; no. 19; pp. 2751 - 2760
• Main Authors: van Steen, Bart J, van Wijngaarden, Ineke, Tulp, Martin T. M, Soudijn, Willem
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.09.1993
• Subjects: Animals; Binding Sites; Brain - drug effects; Brain - metabolism; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Bridged Bicyclo Compounds - metabolism; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Rats; Receptors, Serotonin - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00071a006

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-benzodioxin-5-yl)piperazine (3) and 1-(benzo[b]furan-7-yl)piperazine (4). The linear and branched hydrocarbon chain derivatives up to n-decyl were synthesized and evaluated for their ability to displace [3H]-2-(di-n-propylamino)-8-hydroxytetralin from its specific binding sites in rat frontal cortex homogenates. All compounds displayed a nanomolar affinity for the 5-HT1A receptor. In both series the N-ethyl and N-n-propyl 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 affinity for the central 5-HT1A receptor site, reaching a local maximum for the N-n-hexyl-substituted phenylpiperazines 23 (Ki = 0.50 nM) and 39 (Ki = 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 constant, Ki+, as a more convenient parameter to study the structure-affinity relationships. However, the Ki+ could not account for the specific N4-substituent effects found.