N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable, Selective Melatonin Receptor Ligands

Abstract

The class of N-(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT(2)-selective partial agonist UCM765 (N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses > or =40 mg kg(-1) (s.c.), in spite of its sub-nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC-MS, synthesized, and in vitro tested for their affinity toward MT(1) and MT(2) receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT(2)-selective partial agonist) and a significantly longer half-life in the presence of rat liver S9 fraction.

Drugs for Insomnia beyond Benzodiazepines: Pharmacology, Clinical Applications, and Discovery

“…The compound UCM765 has greater MT 2 receptor affinity (pK i = 10.18) than melatonin (pK i = 9.59) and has about 100-fold higher affinity for the MT 2 receptor than for the MT 1 receptor (pK i = 8.28). UCM924 also displays MT 2 affinity (pK i = 10.2) that is 300-fold higher than for MT 1 (pK i = 6.75), with an intrinsic activity for MT1: IA r -hMT 1 = 0.1; and for MT2: IA r -hMT 2 = 0.4 (Rivara et al, 2009).…”

Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology

“…Since MLT synthesis, and thus its circulating levels as well as the expression of its receptors, follow circadian daily variations, sleep experiments with UCM765 were performed across the entire 24-hour sleep-wake cycle to examine its effects across the light-dark period. 33 Given the short half-life of the compound (T 1/2 = 44 min) due to an extensive first-pass metabolism, 33,84 UCM765 was injected every 4 hours to keep the concentration of the drug within the steady state range. A subcutaneous injection of UCM765 at a dose of 40 mg/kg significantly reduced the latency to NREMS by 59% while increasing the amount of NREMS during the 24-hour period by 38%.…”

Melatonin receptor ligands: A pharmaco‐chemical perspective

“…Nevertheless, the necessity of the validation of melatonin receptors as therapeutic targets in different diseases was disregarded given the abundance of literature, which demonstrated broad‐reaching actions of this hormone on mammalian physiology. From a more fundamental point of view, the lack of support and lack of long‐term vision may explain why (a) the diversity of structure aiming at the receptors is poor; (b) the antibodies only became recently available despite several previous claims in the literature that antibodies were available and useful; (c) the biological stability of new ligands—and antagonists alike—was rarely studied except for the rare few 32,48 that attempted minimal metabolic stability experiments on newly synthesized (agonist) ligands; and (d) the low priority regarding the search and discovery of biologically stable antagonists (MT 1 and/or MT 2 specific).…”