Affinity and Selectivity of Luzindole Analogs in Mouse and Human MT1 and MT2 Melatonin Receptors Transiently Expressed in Mammalian Cells

Abstract

The goal of this study was to compare the binding affinity and selectivity of luzindole [(2‐benzyl N‐acetyltryptamine (NAT)] analogs [5‐methoxy‐NAT; 2‐benzyl‐N‐propionyl‐AT (N‐0889); pmethoxy‐benzyl‐NAT (N‐0890); 2‐p‐methyl‐benzyl‐NAT (N‐0891)] in the mouse (m) and human (h) MT1 and MT2 melatonin receptors transiently expressed in COS‐7 cells. Melatonin competed for 2‐[125I]‐iodomelatonin binding for the mouse [Ki (nM) for mMT1: 0.89 and mMT2: 0.52] and the human [Ki (nM) for hMT1: 0.78 and hMT2: 0.37] melatonin receptors with equal affinity. Ki values for luzindole [Ki (nM) for hMT1: 492.3 and mMT1: 504.7] and its analogs to compete for mMT1 and hMT1 were very similar. However, the affinity of luzindole [Ki (nM): 12.1 vs. 740.3], N‐0889, N‐0890 and N‐0891 for hMT2 receptors was significantly higher than for the mMT2 receptor. N‐0889, luzindole, N‐0890, and N‐0891 showed higher selectivity affinity ratios (Ki MT1/MT2) for the hMT2 than the hMT1 melatonin receptors having 31, 41, 56, and 91 fold differences, respectively. In contrast, their selectivity affinity ratios for the mMT1 and mMT2 melatonin receptors were identical. These results show significant differences between the human and the mouse melatonin receptor in terms of the affinities and selectivity ratios of luzindole and its analogs. We conclude that caution is needed when affinities and selectivity ratios are extrapolated to different species.