Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective β2-adrenergic receptor agonists

Purpose: To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the β2-adrenergic receptor. Results: Out of 21 computationally designed structures 6 compounds were synthesized and characterized for β2-AR binding affinities, subtype selectivities and functional activities. Conclusion: the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with Kiβ2-AR = 0.28 μm, Kiβ1-AR/Kiβ2-AR = 573, EC50cAMP = 3.9 nm, EC50cardio = 16 nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.

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