Luzindole

Luzindole is a melatonin receptor antagonist, with a 25-fold higher affinity for the MEL-1B-R over the MEL-1A-R receptor subtype. Melatonin is a hormone produced endogenously from serotonin (5-HT), and melatonin interaction at the MEL-1B-R receptor is thought to represent a chemical underpinning for circadian rhythm and the sleep-wake cycle. Luzindole MEL-1B-R antagonism is described to modulate functions of melatonin signaling and the relationship between melatonin regulation and neurotransmission. Luzindole blocks melatonin-mediated inhibition of forskolin-stimulated cyclic AMP production in CHO cells. At 1μM Luzindole antagonizes the melatonin-elicited inhibition of calcium-dependent dopamine release, and at higher concentrations (from 1μM to 10μM) affects the response of this dopamine release mechanism to melatonin concentrations (shifts the dose-response curve). Melatonin activation of the MEL-1B-R receptor advances the circadian rhythm, and antagonism by Luzindole shows a similar shift in the dose-response curve for the response of biological timing to melatonin concentration, providing evidence that the MEL-1B-R receptor indeed represents a chemical foundation for the circadian timing system. Luzindole significantly antagonizes melatonin-mediated antinociception, suggesting that MEL-1B-R plays a further role as a mediator of melatonin modulation of pain signaling.