Pharmacophoric Search and 3D-QSAR Comparative Molecular Field Analysis Studies on Agonists of Melatonin Sheep Receptors

Abstract

Conformational analysis was used to characterize the agonist pharmacophore for melatonin sheep brain receptor recognition and activation. The molecular geometry shared by all conformations of the selected active ligands was determined. Assuming that all the compounds interact at the same binding site at the receptor level, 2-iodomelatonin pharmacophoric conformation served as a template for the superimposition of 64 structurally heterogeneous agonists constituting the training set used to perform a three-dimensional quantitative structure-activity relationship study via the comparative molecular field analysis method. A statistically significant model was obtained for the totality of the compounds (n = 64, q2 = 0.62, N = 6, r2 = 0.96, s = 0.28, F = 249) with steric, electrostatic, and lipophilic relative contributions of 28%, 35%, and 37%, respectively. The predictive power of the proposed model was discerned by successfully testing the 78 agonist ligands constituting the test set. The model so obtained and validated brings important structural insights to aid the design of novel melatoninergic agonist ligands prior to their synthesis.

Recent Advances in Melatonin Receptor Ligands

“…However, the MT 2 /MT 1 selectivities were relatively similar in both series. While the non-OMe compound 62 was a potent antagonist (IC 50 (Figure 4), showed a profile of binding affinities similar to the other two tetracyclic series. Surprisingly, no agonistic activity was detected in the Xenopus assay in any of these compounds and all analogues including the methoxy and ethoxy derivatives were antagonists.…”

“…The tetralines were described generally as equipotent to the corresponding naphthalenes [48]. Other bioisosteric replacements of the indole ring of melatonin with a benzofuran and benzothiophene moiety (compounds 4 and 5 (Figure1), respectively) resulted in a slight loss in affinity [49,50]. However, substitution of the melatonin indole ring with benzimidazole, i.e.…”

“…However, substitution of the melatonin indole ring with benzimidazole, i.e. the formal replacement of C3 with N, dramatically reduced binding affinity [50]. The minimal structural requirement for receptor recognition represent phenylalkyl amides, [51], exemplified by compound 6, which demonstrated remarkably high affinity (K i ϭ 5.5 nM) in chicken brain despite its simplicity.…”

Effect of pyridyl nitrogen on the conformational landscape of 7-azaserotonin: A computational study

“…The presence of the potent Hbond acceptor pyridyl nitrogen in 7-azaserotonin makes it biologically interesting, like 7-azaindole and its analogs [15]. It is also evident from the QSAR and photophysical study on 7-azamelatonin (which has similar structure as that of 7-azaserotonin) that it is a potential probe for receptor recognition [16,17]. As far as the authors are aware there is no such QSAR study on 7-azaserotonin, but the additional H-bond acceptor site in 7-azaserotonin compared to serotonin may enhance the ability of binding 7-azaserotonin to receptor site, so that the 7-azaserotonin may act as a potential agonist or antagonist of serotonin receptor.…”

Correlations of the physicochemical parameters of azaindoles with their reactions

“…The electronic structure and reactivity of azaindoles have been the subject of many reviews [1-4] and original investigations [5][6][7][8][9][10]. Formally, azaindoles are the products of replacing one of the benzene ring carbon atoms with a nitrogen atom [1,11].…”