An analysis of the structure-activity relationship in the adrenergic blocking activity of the beta-haloalkylamines.

Abstract The work of Hall on the correlation of base strengths of aliphatic amines using Taft's polar constant, σ∗, has been extended. It has been shown that the pKa values for 92 amines can be correlated in a single two-parameter equation using σ∗ and nH, where nH indicates the number of hydrogen atoms on the protonated amino nitrogen. This relation can then form the basis for correlating chemical structure and biological activity of amines. In this paper the antagonism of adrenaline, noradrenaline and 5-hydroxytryptamine (5-HT) by a variety of 2-bromo-2-phenylalkylamines is considered. It is shown that substitutents on the aromatic ring are involved in hydrophobic bonding, while those on nitrogen do not seem to influence the biological activity in this fashion. The function of the nitrogen substituents appears to be limited to that of regulating the availability of the lone-pair electrons for immonium ion formation and for its reactivity. The compactness of the nitrogen substituents is shown to be necessary for high adrenergic blocking activity. Possible ways of molecular modification for more active compounds are suggested.

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