MT₁‐Selective Melatonin Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Dynamics Investigation of N‐{[(3‐O‐Substituted)anilino]alkyl}amides

Abstract

The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2-selective antagonists. We synthesized a new series of N-(anilinoalkyl)amides bearing 3-arylalkyloxy or 3-alkyloxy substituents at the aniline ring, looking for new potent and MT1-selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT1 binding affinity (pKi=8.93) and 78-fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3-arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the β2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents.

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.…”

“…This will ultimately allow for the development of selective pharmacotherapeutic treatment strategies in patients with sleep and time shifting disorders. To date, structure-activity relationships conferring selectivity for the MT 1 receptor subtype are still a work in progress; 8 therefore, no selective MT 1 receptor agonists have been tested in sleep and time shifting studies.…”

“…Structural determinants that confer MT 1 or MT 2 binding selectivity have only recently been elucidated. 8,9 Therefore, only a few selective ligands have been reported in the literature, especially with respect to MT 1 receptors; none of these ligands has been tested in vitro in cells or tissues expressing MLT receptors, and their efficacy in the treatment of neuropsychiatric diseases has been poorly evaluated. Other effects of MLT described in the literature include its neuroprotective, [10][11][12] antiinflammatory, 13,14 pain modulatory, 15 retinal, 16 vascular, [17][18][19] antitumour 20 and antioxidant 21 properties.…”

MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective

“…Researchers have been successful at discovering high-affinity and selective ligands for the MT 2 receptor (3); however, there is a lack of selective MT 1 receptor ligands with high efficacy (22). The MT 1 selective ligands available are either antagonists or partial agonists with high selectivity for human recombinant MT 1 receptors in competition for 2-[ 125 I]-iodomelatonin binding; this selectivity is significantly reduced in functional studies (23).…”

Melatonergic drugs in development

“…Both compounds behave as partial MT 1 /MT 2 agonists, as assessed through [ 35 S]GTPγS binding analysis. A structurally-related series of N -(anilinoalkyl)amides, bearing 3-arylalkyloxy substituents, was also examined 104. The highest selectivity was found for compound 11 (Figure 3), which was 78-fold more selective towards MT 1 (MT 1 : K i =1.17 nM; MT 2 : K i =91.2 nM), acting as a partial agonist at both receptor subtypes.…”