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

Authors

  • Prof. Silvia Rivara,

    1. Dipartimento di Farmacia, Università degli Studi di Parma, V.le G. P. Usberti 27A, 43124 Parma (Italy)
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  • Dr. Daniele Pala,

    1. Dipartimento di Farmacia, Università degli Studi di Parma, V.le G. P. Usberti 27A, 43124 Parma (Italy)
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  • Dr. Alessio Lodola,

    1. Dipartimento di Farmacia, Università degli Studi di Parma, V.le G. P. Usberti 27A, 43124 Parma (Italy)
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  • Prof. Marco Mor,

    1. Dipartimento di Farmacia, Università degli Studi di Parma, V.le G. P. Usberti 27A, 43124 Parma (Italy)
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  • Dr. Valeria Lucini,

    1. Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano (Italy)
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  • Dr. Silvana Dugnani,

    1. Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano (Italy)
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  • Prof. Francesco Scaglione,

    1. Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano (Italy)
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  • Dr. Annalida Bedini,

    1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (Italy)
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  • Dr. Simone Lucarini,

    1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (Italy)
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  • Prof. Giorgio Tarzia,

    1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (Italy)
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  • Prof. Gilberto Spadoni

    Corresponding author
    1. Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (Italy)
    • Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino (Italy)
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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.

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