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Abstract
A series of substituted isoquinolinones were synthesized and their binding affinities and functional activities towards human melatonin MT1 and MT2 receptors were evaluated. Structure-activity relationship analysis revealed that substituted isoquinolinones bearing a 3-methoxybenzyloxyl group at C5, C6 or C7 position respectively (C5>C6>C7 in terms of their potency) conferred effective binding and selectivity toward the MT2 receptor, with 15b as the most potent compound. Most of the tested compounds were MT2-selective agonists as revealed in receptor-mediated cAMP inhibition, intracellular Ca2+ mobilization and phosphorylation of extracellular signal-regulated protein kinases. Intriguingly, compounds 7e and 7f bearing a 4-methoxybenzyloxyl group or 4-methylbenzyloxyl at C6 behaved as weak MT2-selective antagonists. These results suggest that substituted isoquinolinones represent a novel family of MT2-selective melatonin ligands. The position of the substituted benzyloxyl group, and the substituents on the benzyl ring appeared to dictate the functional characteristics of these compounds.
Highlights
Melatonin (N-acetyl-5-methoxytryptamine) is a versatile hormone which regulates circadian rhythm as well as many other biological functions [1,2,3]
Competitive receptor binding characteristics of melatonin and the 15 tested compounds towards human MT1 and MT2 stably expressed in Chinese hamster ovary (CHO) cells were determined using intact cell preparation pre-incubated with 1 nM [3H]melatonin
While the difference between 3-methoxybenzyloxyl (7b, 14b, and 15b) and 3,5-di-methoxybenzyloxyl (7c, 14c, 15c) derivatives were obvious, the difference of the extracellular signal-regulated protein kinases (ERK) phosphorylation responses induced by 15b was only slightly better than 15c. These results further suggested that the 3,5-dimethoxybenzyloxyl substituent was better tolerated when located at C5 of the isoquinolinone scaffold
Summary
Melatonin (N-acetyl-5-methoxytryptamine) is a versatile hormone which regulates circadian rhythm as well as many other biological functions [1,2,3]. It is secreted by the pineal gland and its biological effects are exerted through specific melatonin binding sites. Two of them belong to the family of seventransmembrane-domain G protein-coupled receptors (GPCR) have been cloned (MT1 and MT2), and shown to be expressed in mammals [4,5,6]. While the melatonin receptor subtypes may work in concert to regulate various chronobiotic and homeostatic responses, the distinct roles of MT1 and MT2 spur the interest to develop subtype-specific pharmacological agents to pinpoint their individual roles in the regulation of circadian rhythmicity, or promoting sleep without phaseshifting the circadian clock
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