| Abstract
| - Structural modifications of 1, a postsynaptic 5-HT1A receptor antagonist, provided its flexible(8, 12) and rigid (7, 9, 11, 13) analogues. Compounds 7, 8, 9, and 11 showed high 5-HT1A receptoraffinity (Ki = 4−72 nM). They acted as 5-HT1A postsynaptic receptor antagonists, since, like 1,they inhibited the behavioral syndrome, i.e., flat body posture (FBP) and forepaw treading(FT), in reserpine-pretreated rats as well as the lower lip retraction (LLR) in rats, both inducedby 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), a 5-HT1A receptoragonist. Compound 12, which demonstrated high 5-HT1A receptor affinity (Ki = 50 nM), revealedproperties of a partial 5-HT1A receptor agonist: it induced LLR and, at the same time, inhibitedFT in rats. Compound 13 (Ki = 1600 nM) was not tested in a behavioral study. Restriction ofthe conformational freedom in 2, a full 5-HT1A receptor antagonist, yielded compound 14 withhigh 5-HT1A receptor affinity (Ki = 47 nM) and partial agonist properties at postsynaptic 5-HT1Areceptors in the above tests in vivo; i.e., it induced LLR and inhibited FBP and FT in rats.New constrained analogues of 1 and 2 (compounds 7 and 14, respectively) were also synthesizedto recognize a bioactive conformation of those 5-HT1A receptor antagonists. On the basis of invitro and in vivo investigations, binding and functional properties of compound 7 were foundto reflect those of 1 at 5-HT1A receptors. On the other hand, compound 14, a rigid analogue of2, showed a different activity in vivo in comparison with the parent compound. PM3 and MMcalculations revealed the existence of three low-energy conformers of 7 and six of 14, all ofthem belonging to the extended family of conformations. The optimized structures of bothanalogues had a different angle between aromatic planes of terminal fragments; moreover,the heteroaromatic system of those molecules occupied various space regions. Our present studyprovides support to the hypothesis that the bioactive conformation of 1, responsible for itspostsynaptic 5-HT1A receptor antagonism, is an extended linear structure represented by 7.
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