Vol 4 n° 4 - Drug Development
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n higher vertebrates that are active during the day (eg, humans, chicks, and dogs, but not rats, which are nocturnal), nighttime melatonin secretion is temporally associated with sleep.Analysis of 24-h urine samples from young and elderly people alike (Figure 1), with or without insomnia, clearly shows a direct correlation between sleep and urinary excretion of 6-sulfatoxymelatonin.1 Subjects with insomnia have a considerably reduced production of melatonin  from  their  pineal  gland, which  is  due  to  a decrease in the level of the enzyme serotonin N-acetyl- transferase (NAT). Insomnia could therefore be due to a lack of this NAT enzyme in the pineal gland. These observations have led several groups to propose treating sleep disorders by administration of melatonin or melatoninergic compounds, in order to compensate for the lack of melatonin observed in subjects with insomnia. Pineal melatonin secretion in humans We have demonstrated that melatonin is a bioprecursor of hypnotic acetyl metabolites produced by enzymatic acetyl- ation of melatonin and 2-oxomelatonin under the control of acetyltransferases, most probably the NAT enzymes. In 1994, in our laboratory, we developed a specific and highly sensitive gas chromatography–mass spectrometry (GC-MS) method2 to assay, simultaneously and distinctly, plasma concentrations of endogenous melatonin (D0- melatonin) and exogenous melatonin (D7-melatonin), in which 7 atoms of H have been substituted by 7 atoms of deuterium. Using the same human volunteers (12 young subjects in June 1994 and 12 elderly subjects in October 1994), we determined the pharmacokinetics of exogenous 3 9 5 B a s i c   r e s e a r c h Pharmacokinetic  studies  of  melatonin  in  young  and elderly human volunteers, and the measurement of hyp- notic effects in chicks under alternate light–dark or per- manent light conditions, show that melatonin is a bio- precursor of hypnotic acetyl metabolites produced by the enzymatic acetylation of both melatonin and 2-oxomela- tonin under the control of serotonin N-acetyltransferases (NATs), which are present in the pineal gland. The acetyl metabolite of melatonin, which we call carbo2, is an N- acetyl- -carboline. The electroencephalographic (EEG) architecture of the sleep produced by this compound is similar to that of physiological sleep, and is characterized by the significant proportion of slow-wave deep sleep and rapid eye movement sleep. This is in sharp contrast to the EEG sleep architecture observed with GABAergic (GABA, -aminobutyric  acid)  compounds.  Since  insomnia  and sleep disorders are believed to be due to a lack of NAT enzymes in the pineal gland, a new therapeutic approach of  sleep  disorders  by  administration  of  such  hypnotic acetyl  metabolites  of  melatonin,  or  synthetic  analogs thereof, can be envisaged. Dialogues Clin Neurosci. 2002;4:395-401. Role of melatonin in the induction and maintenance of sleep Jean B. Fourtillan, PhD Keywords:  melatonin;  acetylation;  N-acetyltransferase;  sleep;  hypnotic  effect; chick; beagle Author affiliations: Professor of Medicinal Chemistry, Faculty of Medicine and Pharmacy, University of Poitiers, France; Macef SA Research Center, 1, rue des Piliers de Tutelle, Bordeaux, France. Address for correspondence: Jean B. Fourtillan, PhD, 1, rue des Piliers de Tutelle, 33000 Bordeaux, France (e-mail: jean-bernard.fourtillan@macef.net) I