Conformational Restriction in Novel NAN‐190 and MP3022 Analogs and Their 5‐HT 1A Receptor Activity

• 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
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200600009

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.