THE CHEMICAL BASIS FOR ADRENERGIC BLOCKING ACTIVITY IN COMPOUNDS RELATED TO DIBENAMINE

¹ Department of Pharmacology, University of Utah College of Medicine, Salt Lake City, Utah
² Research Laboratories of Givaudan-Delawanna, Inc., Delawanna, N. J.

Certain chemical and pharmacological properties of 113 compounds chemically related to Dibenamine are presented and discussed as representative of a much larger series studied in the same manner.

It is concluded that the highly specific adrenergic blocking activity of members of the Dibenamine series can be adequately explained on the basis of a few specific requirements of chemical structure. To be active a compound must meet the following requirements:

1. It must be a tertiary amine or the quaternary derivative of an active amine.

2. It must include at least one -haloalkyl group capable of forming an intermediate ethylenimmonium (or vinyl) derivative.

3. It must include an unsaturated ring substituent attached to the amine in such a way as to allow resonance stabilization of the active intermediate.

4. In the case of benzyl derivatives, there must be no substitution on the phenyl ring which tends to be out of the plane of the ring.

Compounds meeting these conditions were found to be active, and no compound failing to meet all these requirements could be shown to produce significant Dibenamine-type adrenergic blockade.

The very low toxicity of Dibenamine and most of its active congeners appears to be due to three factors:

1. The presence of only one -haloalkyl moiety.

2. Their low aqueous solubility.

3. The reduced reactivity of their ethylenimmonium (or vinyl) intermediates as a result of resonance stabilization.

Although the chemical basis for activity outlined in this report cannot be considered as definitive, it has proved most helpful in directing the synthesis of a large number of active compounds and should provide useful direction in the development of new -haloalkylamine adrenergic blocking agents of experimental and clinical value. It should also serve to focus attention upon the importance of the chemical properties of pharmacologically active agents, which in the past have been almost completely neglected in favor of physical (steric) properties.

This article has been cited by other articles:

				J. F. Kerwin, G. C. Hall, M. Nickerson, W. S. Gump, R. A. McLean, E. J. Fellows, and G. E. Ullyot The Reported Adrenergic Blocking Action of beta-Haloethylammonium Compounds Science, March 23, 1951; 113(2934): 315 - 317. [PDF]