QSAR models on H₄ receptor antagonists associated with inflammation and anaphylaxis

Abstract

Histamine, an endogenous amine is implicated in hypersensitivity (allergic) responses, gastric acid secretion, neurotransmission, immuno-modulation, cell differentiation, and embryonic development. It exerts its effects via four histamine receptor subtypes, termed H₁ to H₄ receptors (H₁R–H₄R) belonging to the superfamily of G-protein coupled receptors. The latest discovered histamine receptor, H₄R, is implicated in the chemotaxis of several cell types and strongly associated with immune and inflammatory responses. Thus, we found interesting to analyze in terms of 2D-QSAR a number of H₄ antagonists in order to highlight the most important physicochemical properties implicated in their mechanism of action and in continuation to suggest structural modifications. The C-QSAR platform of Biobyte has been used in this study. The study reveals that lipophilicity, clog P (linear or bilinear model) as well as steric factors such as the overall molar refractivity (CMR), molar volume or the substitutents molar refractivity (linear) or the sterimol parameters B₁ and B₅ are important. Electronic effects appear only in one model. The study shows that log P as calculated from the C-QSAR program of Biobyte is suitable for this form of QSAR study.

Keywords:

• QSAR
• histamine antagonists
• lipophilicity
• steric factors
• electronic effects

Acknowledgments

The authors are grateful to Dr. A. Leo and Biobyte Corp. 201 West 4th Str., Suite 204, Claremont CA California, 91711, USA for free access to the C-QSAR program.