Biochemical and Pharmacological Activities of SR 142948A, a New Potent Neurotensin Receptor Antagonist

SR 142948A, 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylc arbamoyl)-2-isopropylphenyl)-1H-pyrazole3-carbonyl]amino] adamantane-2-carboxylic acid, hydrochloride, a new and extremely potent neurotensin (NT) receptor antagonist, has been characterized in comparison with SR 48692. This selective compound possesses nanomolar affinities for NT receptors, recognizes the two binding sites described for the NT receptor and fully displaces [3H]SR 48692 specific binding. SR 142948A antagonizes the classical in vitro NT effects, 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 unilateral intrastriatal injection of NT in mice, with the biphasic profile previously seen for SR 48692. At 0.1 mg/kg (i.p.), it completely antagonizes NT-evoked acetylcholine release in the rat striatum. In contrast to SR 48692, SR 142948A (p.o.) blocks both hypothermia and analgesia 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 bioavailability, 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 exploration of the therapeutic potential of this class of compounds.