Conformational restriction in novel NAN-190 and MP3022 analogs and their 5-HT(1A) receptor activity

The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist a...

Full description

Saved in:
Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 2006-09, Vol.339 (9), p.498-506
Main Authors: Paluchowska, Maria H, Bugno, Ryszard, Charakchieva-Minol, Sijka, Bojarski, Andrzej J, Tatarczyńska, Ewa, Chojnacka-Wójcik, Ewa
Format: Article
Language:English
Subjects:
Animals
Binding, Competitive
Drug Evaluation, Preclinical - methods
Lip - drug effects
Lip - physiology
Male
Molecular Conformation
Molecular Structure
Piperazines - chemistry
Piperazines - pharmacology
Rats
Rats, Wistar
Receptor, Serotonin, 5-HT1A - metabolism
Serotonin 5-HT1 Receptor Agonists
Serotonin Receptor Agonists - chemistry
Serotonin Receptor Agonists - pharmacology
Structure-Activity Relationship
Triazoles - chemistry
Triazoles - pharmacology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist and agonist, respectively. The conformational restriction in the tested structures caused alternations in the observed in vivo effects; compounds 4b and 5b were classified as an inactive agent and an antagonist of postsynaptic 5-HT(1A )receptors, respectively. Rigidification of MP3022 and its 5,6-dimethyl analog structures resulted in cis and trans stereoisomers 6b-9b with a 1- and 2-substituted benzotriazole moiety. In both series, in vitro experiments showed that the cis configurations of the compounds were better tolerated by 5-HT(1A) receptor sites than the trans ones. The conformational analysis revealed various spatial regions that can be explored by terminal benzotriazole fragments in those structures. Like the previously described cis-6b, the new ligand cis-7b, displayed features of a postsynaptic 5-HT(1A) receptor agonist, whereas cis-8b was characterized as a partial agonist of those receptor sites. It was suggested that the nonlinear geometry of the above agents has significant influence on the postsynaptic 5-HT(1A )receptor stimulation.
ISSN:0365-6233