Add time:08/18/2019         Source:sciencedirect.com

Starting with the structure of potent 5-HT1A ligands, that is, MM77 [1-(2-methoxyphenyl)-4-(4-succinimidobutyl)piperazine, 4] and its constrained version 5 (MP349), previously obtained in our laboratory, a series of their direct analogues with differently substituted aromatic ring (R = H, m-Cl, m-CF3, m-OCH3, p-OCH3) were synthesized. The flexible and the corresponding 1e,4e-disubstituted cyclohexane derivatives were designed in order to investigate the influence of rigidification on 5-HT1A affinity, selectivity for 5-HT2A, 5-HT7, D1, and D2 binding sites and functional profile at pre- and postsynaptic 5-HT1A receptors. The new compounds 19–25 were found to be highly active 5-HT1A receptor ligands (Ki = 4–44 nM) whereas their affinity for other receptors was: either significantly decreased after rigidification (5-HT7), or controlled by substituents in the aromatic ring (α1), or influenced by both those structural modifications (5-HT2A), or very low (D2, Ki = 5.3–31 μM). Since a distinct disfavor towards rigid compounds was observed for 5-HT7 receptors only, it seems that the bioactive conformation of chain derivatives at those sites should differ from the extended one.Several in vivo models were used to asses functional activity of 19–25 at pre- (hypothermia in mice) and postsynaptic 5-HT1A receptors (lower lip retraction in rats and serotonin syndrome in reserpinized rats). Unlike the parent antagonists 4 and 5, all the new derivatives tested were classified as partial agonists with different potency, however, similar effects were observed within pairs (flexible and rigid) of the analogues. The obtained results indicated that substitution in the aromatic ring, but not spacer rigidification, controls the 5-HT1A functional activity of the investigated compounds. Moreover, an o-methoxy substituent in the structure of 5 seems to be necessary for its full antagonistic properties. Of all the new compounds studied, trans-4-(4-succinimidocyclohexyl)-1-(3-trifluoromethylphenyl)piperazine 24 was the most potent 5-HT1A receptor ligand in vitro (Ki = 4 nM) and in vivo, with at least 100-fold selectivity for the other receptors tested.

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