N-(Substituted-anilinoethyl)amides: Design, Synthesis, and Pharmacological Characterization of a New Class of Melatonin Receptor Ligands

Abstract

A novel series of melatonin receptor ligands, characterized by a N-(substituted-anilinoethyl)amido scaffold, along with preliminary structure-activity relationships (SARs), is presented. MT1 and MT2 receptor binding affinity and intrinsic activity have been modulated by the introduction of different substituents on the aniline nitrogen, on the benzene ring, and on the amide side chain. Modulation of intrinsic activity and MT2 selectivity of the newly synthesized compounds has been achieved by applying SAR models previously developed, providing compounds with different binding and intrinsic activity profiles. Compound 3d, with a bulky ss-naphthyl group, behaves as an MT2-selective antagonist with sub-nM affinity. Size reduction of the substituent enhances intrinsic activity, as in the nonselective N-methyl-anilino agonist 3i. The phenyl derivative 3g is an MT2-selective partial agonist, with MT2 binding affinity higher than melatonin, showing promising sleep-promoting and antianxiety properties in animal models.

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

“…Very few selective MT 1 receptor agonists have been reported until now. 8 On the contrary, since structure-activity relationships for the binding at the MT 2 receptor are quite consolidated, 44 44 the MT 2 full agonist IIK7, 46 and the MT 2 antagonists 4-phenyl-2-propionamidotetralin (4P-PDOT) 47 and K-185. 46 Figure 1 shows the chemical structure and the binding affinity of these ligands to the human MT 1 and MT 2 receptors.…”

“…44 Even though the indole 46 The antagonist 4P-PDOT is a tetralin derivative with antagonist properties and high selectivity toward MT 2 receptors (300-fold higher than the MT 1 receptor). 47 Of note, even though at the present moment it is the most used MT 2 receptor antagonist, it should always be kept in mind that depending on the assay and the concentration, 4P-PDOT may also act as a weak partial agonist.…”

“…1). Importantly, while UCM765 is an MT 2 partial agonist (α = 0.6) that possesses 100-fold higher affinity for MT 2 than MT 1 receptors, 33,44 IIK7 is an MT 2 full agonist with 90-fold higher affinity for MT 2 than MT 1 receptors. 49 Even though experiments comparing the sleep-promoting properties of the 2 compounds have not yet been conducted, it is important to remember that partial agonists, thanks to their "flexible" properties compared with full agonists, are becoming more and more popular in psychopharmacology.…”

Promotion of Non-Rapid Eye Movement Sleep and Activation of Reticular Thalamic Neurons by a Novel MT2Melatonin Receptor Ligand

“…UCM765 is a novel partial agonist exhibiting greater affinity for MT 2 (pK i ϭ 10.18) than for MT 1 receptors (pK i ϭ 8.38), and even greater MT 2 affinity than MLT itself (pK i ϭ 9.62) (Rivara et al, 2007). UCM765 does not display significant affinity for other receptors, ion channels, and transporters, including those known for their involvement in sleep-wake regulation, such as GABA A , 5-HT2 A , and histamine receptors (data are from Cerep, Celle L'Evescault, France; data not shown).…”

“…In the present study, we examine the effects of the partial MT 2 receptor agonist N-{2- [(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765) (Rivara et al, 2007) on the sleep-wake cycle of rats and that of mice lacking MT 1 or MT 2 receptors, disclosing a selective NREMS promoting effect of UCM765. In addition, having found MT 2 receptors to be abundant in the reticular thalamic nucleus (Rt), we combined extracellular recording in anesthetized rats, as well as bilateral intrathalamic microinfusion and EEG/EMG recording in freely moving rats, to demonstrate that UCM765 induces NREMS by modulating the electrical activity of Rt.…”