INVESTIGATION OF THE MECHANISM OF ACTION OF THE LIPOLYTIC AGENT 4-(3, 4-DIMETHOXYBENZYL)-2-IMIDAZOLIDINONE (Ro 7-2956)

¹ Biological Research Division, Hoffmann-La Roche, Inc., Nutley, New Jersey

Ro 7-2956 elevated serum free fatty acid levels and stimulated glycerol and free fatty acid release from isolated fat cells of the rat. Attempts were made to compare its effects with those of norepinephrine and theophylline. The relative resistance of the Ro 7-2956-induced lipolytic response to the blocking action of propranolol and the failure of this drug to activate erythrocyte adenyl cyclase negate its role as a beta agonist. However, its effects in combination with imidazole or nicotinic acid left doubts that Ro 7-2956 was theophylline-like. Even though theophylline had greater lipolytic potency than Ro 7-2956, the lipolytic response to a combination of adenosine-3',5'-cydlic phosphate with theophylline was less than the sum of each, whereas that of a combination with Ro 7-2956 was greater. Although both theophylline and Ro 7-2956 inhibited phosphodiesterase, the order of potency for lipolysis was the reverse of that for inhibition. It is concluded that the lipolytic response to Ro 7-2956 could result from its inhibition of phosphodiesterase but that the response to theophylline must involve other factors.