Clinical investigation of
melatonin agonists has been hampered by side effects such as
hypothermia,
hypotension and
bradycardia. The availability of a
melatonin agonist devoid of these side effects would improve our understanding of the mechanisms by which
melatonin agonists affect sleep. This study investigated the pharmacokinetics, pharmacodynamics and safety of the
melatonin agonist
beta-methyl-6-chloromelatonin at doses up to 100 mg in healthy volunteers. The design was a single blind, across subjects, placebo controlled, group wise dose escalation using doses of 20, 35, 50 and 100 mg
beta-methyl-6-chloromelatonin. Eight subjects received one dose of study
drug or placebo. Pharmacokinetic analysis showed a consistent Tmax across all doses with a mean of 1.12 +/- 0.11 hr for all groups (mean +/- SD). The half-life was also consistent across dose, with a mean of 1.04 +/- 0.04 hr. Maximum plasma concentrations increased with increasing dose with values of 44.83 +/- 29.79, 100.3 +/- 41.08, 79.84 +/- 26.36 and 410.3 +/- 129.4 ng/ml at doses of 20, 35, 50 and 100 mg, respectively. Area under the curve showed similar increases. No consistent changes in vital signs occurred as a function of dose or time after study
drug. The incidence of all adverse events, the severity of the event or the event's relationship to treatment did not increase with higher doses of
beta-methyl-6-chloromelatonin.
Sleepiness was reported after all doses of
beta-methyl-6-chloromelatonin.
beta-methyl-6-chloromelatonin appears safe and well tolerated at doses up to 100 mg. These doses are not associated with
hypothermia,
bradycardia or
hypotension. A
melatonin agonist lacking these side effects should allow investigation of the direct soporific effects of
melatonin agonists.