Function of BIM 189 As An Antagonist

2018-10-09

Introduction 

BIM 189 is one of the most potent bombesin antagonists known in the guinea pig and 3T3 cell systems but has 40% partial agonist activity in the rat. More recent analogues of this type which were found previously to be even more potent pure antagonists in the guinea pig pancreas or 3T3 cells, exhibited similarly higher binding affinity for rat acini but displayed even higher residual partial agonist activity in the rat.

Pharmacologic action

The ability of BIM 189, a new bombesin antagonist, the receptor for which is not yet known, is to inhibit the satiety effect induced by bombesin and BIM 187. BIM 189 has higher binding affinities for both rat and guinea pig pancreatic acini and is a pure antagonist for both cell types. Alteration of the stereochemistry of the position of 14 amino acid in BIM 189 had somewhat lowered binding affinities but increased pure antagonist properties.

Function

BIM 189 appeared as a potent antagonist of bombesin on feeding behavior. BIM 189 could be either a antagonist or a partial agonist, depending on the dose. BIM 189 (20 mg/kg) inhibits the effect of bombesin but not of BIM 187. BIM 189 may be rather specific and inhibit the bombesin-high affinity receptor more potently, whereas it has less affinity for the receptor through which BIM 187 exerts its action. BIM 187, a new bombesin agonist, induced a significant reduction of food intake when given through i.p. This effect was comparable to the bombesin effect. However, BIM 187 and bombesin differed in terms of dose-effect relationship and time course of the effect. The effect of bombesin was clearly dose-dependent. The effect of BIM 187 was of the 'all or none' response type, with an apparent threshold between 2 and 4 μg/kg. The effect of these two peptides over time was also different: BIM 187 seemed to have a delayed action at high doses (32 μg/kg). These differences may be due to different pharmacodynamics as well as to different affinities for different receptor subtype stimulation, or mechanism of action.

Pharmacokinetics and metabolism

BIM 189 had no effect alone and this suggests a very slight, if any, action of endogenous bombesin at the beginning of the food intake period, more work should be done to confirm this hypothesis.

References:

Laferrère B, Leroy F, Bonhomme G, et al. Effects of bombesin, of a new bombesin agonist (BIM187) and a new antagonist (BIM189) on food intake in rats, in relation to cholecystokinin.[J]. European Journal of Pharmacology, 1992, 215(1):23-28.

Coy D, Wang L H, Jiang N Y, et al. Short chain bombesin pseudopeptides with potent bombesin receptor antagonist activity in rat and guinea pig pancreatic acinar cells[J]. European Journal of Pharmacology, 1990, 190(1):31-38.

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