MCH-R1 Antagonist GPS18169, a Pseudopeptide, Is a Peripheral Anti-Obesity Agent in Mice

Abstract

Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brain of animals, including fishes, batrachians, and mammals. MCH is implicated in appetite and/or energy homeostasis. Antagonists at its receptor (MCH-R1) could be major tools (or ultimately drugs) to understand the mechanism of MCH action and to fight the obesity syndrome that is a worldwide societal health problem. Ever since the deorphanisation of the MCH receptor, we cloned, expressed, and characterized the receptor MCH-R1 and started a vast medicinal chemistry program aiming at the discovery of such usable compounds. In the present final work, we describe GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor with an affinity in the nanomolar range and a Ki for its antagonistic effect in the 20 picomolar range. Its metabolic stability is rather ameliorated compared to its initial parent compound, the antagonist S38151. We tested it in an in vivo experiment using high diet mice. GPS18169 was found to be active in limiting the accumulation of adipose tissues and, correlatively, we observed a normalization of the insulin level in the treated animals, while no change in food or water consumption was observed.

Why Search for Alternative GPCR Agonists?

“…Finally, a more stable version of S38151, GPS18169, comprising unnatural amino acids, was designed. This later was stable and active in vivo in reference rodent models of obesity [81]. A nice transition from bench to preclinical experiments has been developed in this program over a period of nearly 25 years in which a series of peptides designed on the binding and functionality of an agonist of a cloned receptor was transformed into a promising anti-obesity drug candidate.…”

Pharmacotherapy for chronic obesity management: a look into the future

“…Melanin-concentrating hormone (MCH) is a 19 amino acid long peptide found in the brains of several mammalian species and has been implicated in appetite control and energy homeostasis. GPS18169, a pseudopeptide antagonist at the MCH-R1 receptor has been shown to reduce adiposity and normalise insulin levels in mice fed a high fat diet with no change in food or water consumption [93].…”

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

“…The first MCHR1 antagonists were also peptidic, and these were utilized in a number of pioneering basic science studies (see MacNeil and Bednarek, 2009 ). At least one clinically-oriented drug development program has focused on pseudopeptide antagonists of MCHR1 (Servier, see Boutin et al, 2021 ); however, peptides are generally susceptible to proteolytic degradation and have limited ability to cross cellular membranes/blood-brain barrier (BBB), and are therefore considered inferior to small-molecules for most clinical applications. The first small-molecule MCHR1 antagonist was reported in 2001 (from Haynes et al, 2001 ).…”