Molecular Pharmacology, Vol 12, 701-710, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

The Pharmacological Effects of Conjugates of Pharmacologically Active Amines to Complex or Simple Carriers: a New Class of Drug

¹ Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, and the Cardiovascular Research Institute, University of California, San Francisco, California 94143; and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014

Conjugation of selected amines to rabbit serum albumin or copolymer carriers (via amide bonds by sp³ C-N bonds generated by reduction of glutaraldehyde-amine Schiff bases) forms compounds that differ chemically from the free hormones. However, when histamine is conjugated to carrier, by either the carbodiimide or the glutaraldehyde sequence, the pharmacological properties of the conjugate resemble those of free histamine in that both stimulate accumulation of adenosine cyclic 3',5'-monophosphate (cAMP) in human leukocytes. Additionally, the effects of the histamine conjugates are blocked by antihistamines but are unaffected by adrenergic blocking agents. Amide conjugates of norepinephrine are inactive, but when this amine is conjugated via glutaraldehyde the resulting conjugate, like norepinephrine, stimulates accumulation of cAMP in leukocytes and is antagonized by the beta adrenergic blocker propranolol. Conjugates of congeners of norepinephrine that possess no beta adrenergic activity (e.g., normetanephrine) are inactive on leukocytes. Conjugates of some amines, such as tryptamine and dopamine, do not mimic the action of the corresponding free amines. In some cases, when the nitrogen moiety of the conjugate is converted from a primary to a secondary amine, the amine is able to interact with native leukocyte receptors (i.e., stimulation of adenylate cyclase occurs and is appropriately blocked by competitive antagonists of the free amine). In other cases, the actions of the conjugates could not have been predicted by knowing the pharmacological effects of the parent amine.

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ACKNOWLEDGMENTS The authors acknowledge and appreciate the excellent technical assistance of Ms. Michele Sanda and the editorial assistance of Ms. Emma Ponick.