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

The design of compounds selective for the MT(1) melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT(1) 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 MT(1) /MT(2) agonists and MT(2) -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 MT(1) -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 MT(1) binding affinity (pK(i) =8.93) and 78-fold selectivity for the MT(1) 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 MT(1) receptor based on the β(2) adrenergic receptor crystal structure in its activated state. A binding mode for MT(1) agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT(1) selectivity of compounds with lipophilic arylalkyloxy substituents.