Two novel agents affecting eating through an action on monoaminergic systems

The pharmacological effects of two newly synthesized anorectic agents CM 57373 (4-amino-1-(6-bromopyrid-2-yl) piperidine hydrochloride) and CM 57493 (4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6 tetrahydrophyridine hydrochloride) have been studied. Both drugs decreased food intake dose dependently in rats deprived of food for 20 h/d. The doses that inhibited food intake by 50 percent (ID50) were 9.74 mg kg-1 p.o. for CM 57493 and 7.37 mg kg-1 p.o. for CM 57373. The general behaviour of the rats was not affected at anorectic doses and no amphetamine-like stimulation was observed. The anorectic effect of CM 57373 was selectively, but not completely, antagonized by metergoline and methysergide, two antagonists of serotoninergic receptors in the central nervous system. Neither noradrenaline antagonists (propranolol and phentolamine) nor a dopamine antagonist (penfluridol) affected the anorexia induced by CM 57373. These results indicate that the anorectic effect of CM 57373 is, at least, partially mediated by the serotoninergic system. The mechanism of action of CM 57493 is more complex, since several distinct neurotransmitter systems appear to be involved in its effect. In cross-tolerance experiments with fenfluramine, there was a reduction of the anorectic activity of CM 57493, suggesting similar mechanisms of action for these two drugs, even though pretreatment with metergoline or methysergide antagonized the anorectic effect of fenfluramine but not that of CM 57493. The anorectic effect of CM 57493 was antagonized by pretreatment with propranolol, a beta-noradrenergic antagonist, suggesting an involvement for the beta-noradrenergic system as well. Pretreatment with phentolamine or penfluridol did not modify the effect of CM 57493 on food intake. In-vitro and in-vivo biochemical studies showed that CM 57373 and CM 57493 act mainly on central serotoninergic mechanisms. CM 57373 is a serotonin releaser and a serotonin reuptake inhibitor. But, unlike fenfluramine which affects the storage pool for 5HT, it releases 5HT mainly from a functional pool. CM 57493 did not affect serotonin release and uptake but exhibited a high affinity to serotonin postsynaptic receptors.