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-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.
van Steen
B J
BJ
Department of Medicinal Chemistry and Pharmacology, Solvay Duphar Research Laboratories, Weesp, The Netherlands.
van Wijngaarden
I
I
Tulp
M T
MT
Soudijn
W
W
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001643:Bridged Bicyclo Compounds; D010879:Piperazines; D011985:Receptors, Serotonin