BIOCHEMICAL AND PHARMACOLOGICAL ACTIVITIES OF SR 142948A, A NEW POTENT NEUROTENSIN RECEPTOR ANTAGONIST

SR 142948A, imethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N- -pyrazo le-3-carbonyl]amino}adamantane-2-carboxylic acid, hydrochloride, a new and extremely potent neurotensin (NT) receptor antagonist, has been c haracterized in comparison with SR 48692. This selective compound poss esses nanomolar affinities for NT receptors, recognizes the two bindin g sites described for the NT receptor and fully displaces [H-3]SR 4869 2 specific binding. SR 142948A antagonizes the classical in vitro NT e ffects, i.e., inositol monophosphate formation in HT 29 cells (IC50 = 3.9 nM) or intracellular calcium mobilization in Chinese hamster ovary cells transfected with the human receptor. It dose-dependently (0.04- 640 x 10(-3) mg/kg p.o.) inhibits the turning behavior induced by unil ateral intrastriatal injection of NT in mice, with the biphasic profil e previously seen for SR 48692. At 0.1 mg/kg (i.p.), it completely ant agonizes NT-evoked acetylcholine release in the rat striatum. In contr ast to SR 48692, SR 142948A (p.o.) blocks both hypothermia and analges ia induced by i.c.v. injection of NT (mice and/or rats) but is unable to modify the dopamine release evoked by NT injection into the ventral tegmental area. In summary, SR 142948A retains the properties of the lead compound SR 48692 (no intrinsic agonist activity, oral bioavailab ility, long duration of action and good brain access), reveals a wider spectrum of activity than SR 48692 (probably due to the inhibition of NT receptor subtypes) and represents an additional tool for further e xploration of the therapeutic potential of this class of compounds.