CHARACTERIZATION OF A RETINAL MELATONIN RECEPTOR

  • 1 January 1985
    • journal article
    • research article
    • Vol. 234  (2) , 395-401
Abstract
Melatonin (5-methoxy-N-acetyltryptamine) at pM concentrations (IC50 [mean inhibitory concentration] 40 pM) inhibited the Ca-dependent release of [3H]dopamine elicited at 3 Hz (2 min, 20 mA, 2 ms) from rabbit retina through activation of a site possessing the pharmacological and functional characteristics of a receptor. The effect of melatonin shows biological specificity as this hormones does not modify [3H]dopamine release from striatum or olfactory tubercle. The effects of small modifications of the melatonin structure of the inhibition of Ca-dependent release of [3H]dopamine from retina are described. The more active melatonin analogs were those possessing a 5-methoxy group on carbon 5 of the indole nucleus and an N-acetyl group on the same position as in melatonin. THe potencies of 5-methoxy indoles compounds was as follows (IC50): melatonin (40 pM) = 6-chloromelatonin (40 pM) > 6-hydroxymelatonin (1.6 nM) .gtoreq. 6-methoxymelatonin (2 nM) > 5-methoxytryptamine (63 nM) > 5-methyoxy-N,N-di-methyltryptamine (200 nM) .mchgt. 5-methoxytryptophol (4 .mu.M). The structure activity relationships of melatonin and related indoles indicated that the efficacy of melatonin is determined by the moiety substituted on carbon 5 (i.e., 5-methoxy group); the affinity for the receptor is determined primarily by the moiety substituted on carbon 3 (i.e., ethyl N-acetyl group) of the indole nucleus. N-acetyltryptamine competitively antagonized the inhibitory effect of melatonin in the chicken retina and appears to be a partial agonist in the rabbit retina. The rabbit or chicken retina preloaded in vitro with [3H] dopamine can be used to screen the effect of chemical modifications in the melatonin molecule that may lead to the discovery of potent and selective melatonin receptor agonists and antagonists with therapeutic potential.

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