On the bioactive conformation of NAN-190 (1) and MP3022 (2), 5-HT1A receptor antagonists

Structural modifications of 1, a postsynaptic 5-HT1A receptor antagonist, p rovided its flexible (8, 12) and rigid (7, 9, 11, 13) analogues; Compounds 7, 8, 9, and 11 showed high 5-HT1A receptor affinity (K-i = 4-72 nM). They acted as 6-HT1A postsynaptic receptor antagonists, since, like 1, they inhi bited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw tr eading (FT), in reserpine-pretreated rats as well as the lower lip retracti on (LLR) in rats, both induced by 8-hydroxy-2-(di-n-propylamino)tetralin hy drobromide (8-OH-DPAT), a 5-HT1A receptor agonist. Compound 12, which demon strated high 6-HT1A receptor affinity (K-i = 50 nM), revealed properties of a partial 5-HT1A receptor agonist: it induced LLR and, at the same time, i nhibited FT in rats. Compound 13 (K-i = 1600 nM) was not tested in a behavi oral study. Restriction of the conformational freedom in 2, a full 5-HT1A r eceptor antagonist, yielded compound 14 with high 5-HT1A receptor affinity (K-i = 47 nM) and partial agonist properties at postsynaptic 5-HT1A recepto rs in the above tests in vivo; i.e., it induced LLR and inhibited FBP and F T in rats. New constrained analogues of 1 and 2 (compounds 7 and 14, respec tively) were also synthesized to recognize a bioactive conformation of thos e 5-HT1A receptor antagonists. On the basis of in vitro and in vivo investi gations, binding and functional properties of compound 7 were found to refl ect those of 1 at 5-HT1A receptors. On the other hand, compound 14, a rigid analogue of 2, showed a different activity in vivo in comparison with the parent compound. PM3 and MM calculations revealed the existence of three! l ow-energy conformers of 7 and six of 14, all of them belonging to the exten ded family of conformations. The optimized structures of both analogues had a different angle between aromatic planes of terminal fragments; moreover, the heteroaromatic system of those molecules occupied various space region s. Our present study provides support to the hypothesis that the bioactive conformation of 1, responsible for its postsynaptic 5-HT1A receptor antagon ism, is an extended linear structure represented by 7.