How PF-5190457 expanded alcohol-use-disorder research through the ghrelin receptor

Approved treatments for alcohol use disorder act through several mechanisms. PF-5190457 introduced a different target: growth hormone secretagogue receptor 1a (GHS-R1a), the ghrelin receptor. It was the first reported oral GHS-R1a inverse agonist profiled in humans and was later studied in heavy drinkers.

A receptor inhibited in two ways

GHS-R1a can signal without ghrelin, a property known as constitutive activity. PF-5190457 acts as both an inverse agonist and a competitive antagonist: it suppresses ligand-independent activity while blocking activation by acyl-ghrelin.

This makes the compound available at https://ebc.enamine.net/molecule-product/EBC-499104 useful for comparing inverse agonism with antagonism. A neutral antagonist blocks ligand-driven activation without necessarily reducing constitutive signaling.

A metabolite with a different profile

PF-5190457 produces a hydroxy metabolite, PF-6870961. The metabolite has lower binding affinity and is less potent than its parent at inhibiting GHS-R1a-mediated inositol phosphate accumulation. It is more potent at inhibiting β-arrestin recruitment. These differences suggest signaling bias but do not establish how either pathway affects alcohol-related behavior.

What the clinical studies showed

A Phase 1b study used a single-blind, fixed-order design in 12 heavy drinkers. Doses of 50 or 100 mg twice daily were generally well tolerated with alcohol, and adverse events were mild or moderate. The 100 mg dose was associated with lower craving during a cue-reactivity procedure, while the acyl-to-total ghrelin ratio and IGF-1 were potential pharmacodynamic markers.

This finding was preliminary. A later randomized, double-blind Phase IIa study found no reduction in cue-elicited alcohol craving and no change in neural responses during an fMRI task. Limited brain penetration may help explain the absence of central effects.

Repeated dosing in healthy volunteers also attenuated some peripheral pharmacodynamic responses. The available studies do not show that a central anti-craving effect persisted after peripheral tachyphylaxis.

What the interaction data show

In rats, PF-5190457 did not alter alcohol-related locomotor suppression or loss of the righting reflex, and alcohol did not change blood PF-5190457 concentrations. In humans, the drug did not alter alcohol concentrations or elimination. These results argue against a pharmacokinetic interaction or a nonspecific change in alcohol sedation as the explanation for the preliminary craving result.

PF-5190457 remains a useful probe for studying GHS-R1a in metabolic and alcohol-related behavior. Its tolerability and inverse-agonist pharmacology support further research, but efficacy in alcohol use disorder and the roles of peripheral and central mechanisms remain unproven.