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Distortion and energetics in the agonist conformation bound phenoxypropanolamine agents in the β 1 ‐adrenoceptor
Author(s) -
Wilkinson A. J.,
Timms D.,
Davies R. H.,
Broadley K. J.,
Kelly D. R.
Publication year - 1994
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560520711
Subject(s) - chemistry , dihedral angle , conformational isomerism , anisole , steric effects , moiety , crystallography , stereochemistry , substituent , ring (chemistry) , lone pair , methyl group , molecule , group (periodic table) , hydrogen bond , organic chemistry , catalysis
A theoretically contracted agonist conformation of potent phenoxypropanolamine derivatives on the β 1 ‐adrenoceptor has been analyzed in detail. The main effect of the enthalpic contraction of some 6.0–7.0 kcal/mol arises from the movement of the nitrogen atom toward the aromatic ring by 0.7–0.8 Å, requiring some 3.0–3.5 kcal/mol. A second effect arising from the contraction can be a dihedral rotation of some 30° around the OCH 2 bond of the planar anisole moiety. This rotation is correlated with an effect arising from “in‐plane” deformation of the anisole moiety where opening of the relevant bond angle releases steric constraints for this rotation. Ortho ‐substituents assist this rotation indirectly through hyperconjugation with the lone pair of the OCH 2 group, electron‐attracting substituents opening this bond angle and lowering the energy required to reach a given bond‐angle deformation. The adjacent ring meta ‐substituent can be similarly affected, the strength of the total effect being also of the order of 3.0–3.5 kcal/mol. The net effect gives rise to a further contraction of the nitrogen atom and the betahydroxyl group toward the aromatic ring, the beta‐hydroxyl group showing a contraction of up to 0.4–0.5 Å along the main axis of the conformer. The deformed conformation is consistent with the predicted conformer of a fixed‐ring benzdioxepine molecule that possesses the highest degree of partial agonism within the set of phenoxypropanolamine agents. It is concluded that ortho ‐substituents in phenoxypropanolamine derivatives can retain steric freedom in both agonist and antagonist action provided that the substituent can accommodate the required deformation, both agonist and antagonist conformer forms lying within one unbound conformation. The agonist conformer is consistent with the proposed model for the ligand‐activated transmembrane proton transfer in the β 1 ‐adrenoceptor where a contraction along the main axis of the ligand conformer (with some attendant distortion in the position of the β‐hydroxyl moiety) is required to activate proton transfer. © 1994 John Wiley & Sons, Inc.