Structure-Activity Studies of Melatonin Analogues in Prepubertal Male Rats

Abstract

Comparison has been made between the activity of the pineal hormone melatonin, and several analogues and metabolites in inhibiting sexual development in a protein-restricted prepubertal rat model. Eleven melatonin analogues or metabolites were tested with the aim of evaluating the model as a test of the hypothesis that melatonin acts as a prohormone and that the ring schism metabolites (kynurenamines) mediate many of the effects attributable to melatonin. Although the hypothesis could not be confirmed, modification of the melatonin structure by lengthening the acylamide side chain or by replacing the 5 methoxy function with fluorine resulted in loss of biological potency. Modification of the melatonin structure to block the two known points of metabolism resulted in no significant alteration in biological activity. Thus 6-chloromelatonin (blocking 6-hydroxylation) and 2,3-dihydromelatonin (blocking oxidative cleavage of the C2-C3 bond) and 6-chloro-2,3-dihydromelatonin remained biologically active. The metabolic products of brain indolearnine-2,3-dioxygenase, N-acetyl-N 2 -formyl-5-methoxy kynurenamine (aFoMK) and N-acetyl-5-methoxy kynurenamine (aMK), paradoxically were also biologically active.

N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine, a biogenic amine and melatonin metabolite, functions as a potent antioxidant

“…In the past three decades, only two publications have indicated that AFMK may possess physiological functions (6,7). Considering the potent antioxidant capacity of its precursor melatonin (8)(9)(10) and preliminary data from our observations, we speculated that one physiological role of AFMK may be to function as an endogenous antioxidant.…”

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…AMK decrease sexual development in a prepubertal rat model (Kennaway et al, 1988). It is noteworthy that AFMK accelerates re-entrainment of the 6-hydroxymelatonin rhythm, when given at the new dark onset, after a phase advance of the light/dark cycle in male rats (Kennaway et al, 1989).…”

Metabolism of the Melatonin Metabolite N1-Acetyl-N2-formyl-5-methoxykynuramine in Saccharomyces cerevisiae

“…Guenther et al 2005, Rosen et al 2006, according to Kennaway et al (1988). 3-Acetamidomethyl-6-methoxycinnolinone (AMMC) and N-[2-(6-methoxyquinazolin-4-yl)-ethyl]-acetamide (MQA) (Fig.…”