Adrenergic agents. 5. Conformational analysis of 1-alkylamino-3-aryloxy-2-propanols by proton magnetic resonance studies. Implications relating to the steric requirements of adrenoreceptors.
Two distinct chemical classes, namely, phenylethanolamines resembling the natural biogenic catecholamines and 1-alkylamino-3-aryloxy-2-propanols (aryloxpropanolamines), exert a distinct action as agonists and/or antagonists of adrenergic receptors. To explore the possibility that these two different kinds of chemicals might share a common ground-state conformation as an essential structural feature that satisfies the specific steric requiremetns for the active site of the receptor, a conformational analysis of some aryloxypropanolamines and related compounds was performed. On the basis of this NMR conformational analysis it is suggested that salts of 1-alkylamino-3-aryl-oxy-2-propanols in a nonpolar solvent may exist in a stable "rigid" conformation involving two intramolecular hydrogen bonds to form a 6-5 bicyclic chelated structure. Comparison of steremodels of this "rigid" bicyclic conformer with the conformationally preferred trans (phenyl to amino) rotamer of adrenergic phenylethanolamines, such as isoproterenol, indicates that all positions of the phenyl ring, the phenyl to oxygen or phenyl to carbon bonds, and the ammonium groups of both chemical classes may be superimposed nearly exactly. A major difference between the two species is the relative steric orientation of the alcoholic hydroxyl groups which are about 2 A removed when models of the two classes of adrenergic agents are superimposed. That a specific steric orientation of this alcoholic functionality may not be an absolute requirement for adrenergic activity is supported by the recent observation of significant activity in the homologue of N-tert-butylnorepinephrine in which a methylene group is inserted between the benzylic carbon and the hydroxyl group. Possibly the different steric location of the alcoholic hydroxyl group may be involved in the altered beta1- and beta2-adrenoreceptor selectivity of phenylethanolamines and phenoxypropanolamines.
D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011412:Propanolamines / Q000494:pharmacology; D011941:Receptors, Adrenergic; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013566:Sympathomimetics
D011412:Propanolamines; D011941:Receptors, Adrenergic; D013566:Sympathomimetics