Luzindole (N-0774): A novel melatonin receptor antagonist

The pharmacological potencies of 2-substituted N-acetyltryptamines were determined on the presynaptic melatonin receptor site of rabbit retina labeled in vitro with [³H]dopamine. Calcium-dependent release of [³H]dopamine was elicited by electrical stimulation at 3 Hz for 2 min (20 mA, 2 msec). Melatonin (5-OCH₃-N-acetyltryptamine) and 6-chloromelatonin were equipotent in inhibiting the calcium-dependent release of [³H]dopamine (IC₅₀ = 40 pM). 2-Substituted N-acetyltryptamines with a methyl (i.e., 6,7-dichloro-2-methylmelatonin, IC₅₀ = 10 pM) or iodine (i.e., 2-iodomelatonin, IC₅₀) = 5 pM) group were more potent than melatonin in inhibiting [³H]dopamine release. I report here the pharmacological properties of the novel N-acetyltryptamine, 2-benzyl-N-acetyltryptamine (N-0774, luzindole) on the presynaptic melatonin receptor of rabbit retina. Luzindole (0.1-10 μM) did not affect the spontaneous outflow of radioactivity or the stimulated-evoked release of [³H]dopamine when added alone. However, luzindole (0.1-10 μM) shifted the concentration effect curve for melatonin to the right in a parallel fashion. The pA₂ extrapolated from the Schild plot (slope, 0.91) was 7.7, with a K(B) = 20 nM. The dissociation constants for luzindole (K(B)), determined in the presence of 6,7-dichloro-2-methylmelatonin (10 pM-1 nM) or 6-chloromelatonin (10 pM-100 nM) were 16 and 40 nM, respectively. These data suggest that luzindole and the various melatonin agonists are competing for the same presynaptic melatonin receptor site in the rabbit retina. In summary, 2-substituted 5-methoxy-N-acetyltryptamines (i.e., 6,7-dichloro-2-methylmelatonin, 2-iodomelatonin) are agonists, N-acetyltryptamine is a partial agonist and 2-benzyl-N-acetyltryptamine (i.e., luzindole) is a competitive receptor antagonist at the presynaptic melatonin receptor of rabbit retina.