RADIOLIGAND BINDING-AFFINITY AND BIOLOGICAL-ACTIVITY OF THE ENANTIOMERS OF A CHIRAL MELATONIN ANALOG

Melatonin, a hormone secreted by the pineal gland, can act on the cent ral circadian oscillator in the suprachiasmatic nucleus of the hypotha lamus. It has been proposed that melatonin or its analogues may be use ful in restoring disturbed circadian rhythms in jet-lag, shift-work an d some blind subjects, and as sleep-promoting agents. In the present s tudy, the (-)- and (+)-enantiomers of hyl-6-methoxy-9-methyl-1,2,3,4-t etrahydrocarbazole (AMMTC) were separated and tested. The affinity of the enantiomers at the specific 2-[I-125]iodomelatonin binding site in chick brain membranes was compared in competition assays, and their b iological activity in a specific melatonin receptor bioassay, aggregat ion of pigment granules in Xenopus laevis melanophores. The (-)-enanti omer of AMMTC was 130-fold and 230-fold more potent than the (+)-enant iomer in competition radioligand binding assays and melanophores, resp ectively. Both enantiomers are melatonin receptor agonists; (-)-AMMTC is slightly more potent than melatonin itself. As the tetrahydrocarbaz ole nucleus holds the C-3 amido side-chain of AMMTC in a restricted co nformation, the analogues will be useful in modelling the melatonin re ceptor binding site.