| 16941730 |
Paluchowska MH, Bugno R, Charakchieva-Minol S, Bojarski AJ, Tatarczynska E, Chojnacka-Wojcik E: Conformational restriction in novel NAN-190 and MP3022 analogs and their 5-HT (1A) receptor activity. Arch Pharm. 2006 Sep;339(9):498-506.
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. |
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