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

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 micromol L(-1) caused a prolonged facilitation of the amplitude of cholinergically mediated contractions, to a maximum of 248 +/- 47% at 3 micromol L(-1). In human-isolated stomach, GSK962040 10 micromol L(-1), erythromycin 10 micromol 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.

Sexually differentiated regulation of gnRH release by gonadal steroid hormones in sheep.

Exposure of the sheep fetus to testosterone from day 30 to day 90 of a 147 day gestation causes the neurones that control GnRH secretion, the GnRH neuronal network, to become organized in a sex-specific manner. After androgen exposure in utero, GnRH neurones are activated in a sexually differentiated pattern by gonadal steroid hormones. Specifically, follicular phase concentrations of oestrogen trigger a GnRH 'surge' in ewes, but not in rams or females treated with androgen during fetal life. Furthermore, progesterone is a less potent inhibitor of GnRH release in rams or females treated with androgen during fetal life. The reasons for the sexual differentiation of these steroid feedback mechanisms probably reside in a dimorphism in steroid-sensitive neural inputs to GnRH neurones. The density of neurones containing oestrogen receptor alpha is sexually differentiated in areas of the ovine brain that are known to be involved in the steroidal regulation of GnRH. Furthermore, neurones in these regions are activated in a gender-specific pattern. A determination of the neural phenotype of these steroid-sensitive cells will form a basis for understanding the mechanisms by which the GnRH neuronal network is organized and activated in a sexually differentiated manner.