GSK962040: a small molecule, selective motilin receptor agonist, effective as a stimulant of human and rabbit gastrointestinal motility

Abstract There is an urgent clinical need for a safe, efficacious stimulant of gastric emptying; current therapies include erythromycin (an antibiotic with additional properties which preclude chronic use) and metoclopramide (a 5‐hydroxytryptamine type 4 receptor agonist and an antagonist at brain D₂ receptors, associated with movement disorders). To move away from the complex motilide structure of erythromycin, a small molecule motilin receptor agonist, GSK962040, was identified and characterized. The compound was evaluated using recombinant human receptors, rabbit and human isolated stomach preparations known to respond to motilin and in vivo, by measuring its ability to increase defecation in conscious rabbits. At the human motilin receptor, the pEC₅₀ (the negative logarithm to base 10 of the EC₅₀ value, the concentration of agonist that produces 50% of the maximal response) values for GSK962040 and erythromycin as agonists were, respectively, 7.9 and 7.3; GSK962040 had no significant activity at a range of other receptors (including ghrelin), ion channels and enzymes. In rabbit gastric antrum, GSK962040 300 nmol L^?1–10 μmol L^?1 caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 ± 47% at 3 μmol L^?1. In human‐isolated stomach, GSK962040 10 μmol L^?1, erythromycin 10 μmol L^?1 and [Nle¹³]‐motilin 100 nmol L^?1, each caused muscle contraction of similar amplitude. In conscious rabbits, intravenous doses of 5 mg kg^?1 GSK962040 or 10 mg kg^?1 erythromycin significantly increased faecal output over a 2‐h period. Together, these data show that GSK962040, a non‐motilide structure, selectively activates the motilin receptor. Simplification of the structural requirements to activate this receptor greatly facilitates the design of potentially new medicines for gastroparesis.     

Naloxone-induced antagonism of Mayer waves

The effects of intravenous naloxone and morphine on third-order blood pressure waves (Mayer waves) was investigated in chloralose-anesthetized cats. Naloxone (1–5 mg/kg) reduced effectively the amplitude of Mayer waves and caused a slight reduction in frequency of oscillations. In animals with labile blood pressure, morphine sulfate (1 mg/kg) induced Mayer waves. Naloxone antagonized morphine actions. These results suggest an involvement of endogenous opiate peptides in the pathophysiology of third-order blood pressure waves.