Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor

https://doi.org/10.1016/j.bmcl.2007.10.115Get rights and content

Abstract

A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.

References and notes (14)

  • Ujjainwalla, F. In 230th ACS National Meeting, Washington, DC, U.S.A. 2005; MEDI...
  • R.A. Bucsh et al.

    J. Med. Chem.

    (1993)
    R. Achini

    Helv. Chim. Acta

    (1981)
  • W. Jiang et al.

    Bioorg. Med. Chem. Lett.

    (2007)
  • V.S. Goodfellow et al.

    Curr. Top. Med. Chem.

    (2003)
  • R.D. Cone

    Nat. Neurosci.

    (2005)
  • Y.K. Yang

    Obes. Rev.

    (2003)
There are more references available in the full text version of this article.

Cited by (15)

  • Molecular signatures of human melanocortin receptors for ligand binding and signaling

    2017, Biochimica et Biophysica Acta - Molecular Basis of Disease
    Citation Excerpt :

    Several selective agonists for MC1R, MC3R, MC4R and MC5R were also created [42–46] [47]. Many synthetic small molecular agonists were developed due to the importance of the MCRs in the regulation of human physiology, especially for hMC4R [44,48–56]. These synthetic compounds have different chemical structures compared to that of MSH but they are selective for MC4R.

  • Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

    2017, Biochimica et Biophysica Acta - Molecular Basis of Disease
    Citation Excerpt :

    This compound blocked α-MSH stimulated cAMP production with a IC50 value of 93 nM. Interestingly, the cis-isomers of the pyrrolidine substitution were found to impart higher binding affinity, in contrast to the trans-isomers previously reported when the pyrrolidine nitrogen is in a different location (4 versus 1 and 2, Fig. 3) [147,148]. The group at Neurocrine also investigated a series of piperazinebenzylalcohols and related ketones and amine analogs without the pyrrolidine ring (5, Fig. 3) [150].

  • Subtleties in GPCR drug discovery: A medicinal chemistry perspective

    2012, Drug Discovery Today
    Citation Excerpt :

    MCRs having multiple roles such as energy homeostasis and sexual behavior have been targeted over the past decade [12]. In the discovery program for a selective MC4 receptor agonist, a series of pyrrolidine-based compounds having different stereocenters was reported [13,14]. One kind of compound having (3S, 4R) stereochemistry in the pyrrolidine scaffold (7; Fig. 2) delivered an agonistic response whereas that with opposite stereochemistry (8; Fig. 2) gave an antagonistic response.

  • Acetylcholine binding protein (AChBP) as template for hierarchical in silico screening procedures to identify structurally novel ligands for the nicotinic receptors

    2011, Bioorganic and Medicinal Chemistry
    Citation Excerpt :

    Further SAR elucidation of the currently identified nAChR ligands can not only lead to improvement of binding affinity and modulation of nAChR subtype selectivity, but also to altered functional activity of the ligands. In previous studies, for example, analogues of the nAChR agonist epibatidine have been synthesized with antagonistic activity on nAChRs,34 and subtle chemical changes have been shown to change the functional activity of ligands for other receptors as well.35–38 It is noted that α7 antagonists are useful not only as molecular tools to investigate the pharmacology of the receptor, but also as drug candidates with anti-cancer effects.39

View all citing articles on Scopus

Present address: Department of Medicinal Chemistry, Tanabe Research Laboratories, USA, Inc., 4540 Towne Centre Ct., San Diego, CA 92121, USA.

Present address: Vertex Pharmaceuticals, Inc., 11010 Torreyana Road, San Diego, CA 92121, USA.

View full text