Characterization of binding sites of a new neurotensin receptor antagonist, [ [formula omitted]]SR 142948A, in the rat brain

• Published in: European journal of pharmacology 1998-02, Vol.343 (1), p.67-77
• Main Authors: Betancur, Catalina, Canton, Maryse, Burgos, Alain, Labeeuw, Bernard, Gully, Danielle, Rostène, William, Pélaprat, Didier
• Format: Article
• Language: English
• Subjects: [ [formula omitted]]SR 142948A; Adamantane; Adamantane - analogs & derivatives; Adamantane - metabolism; Animals; Autoradiography; Binding Sites; Biological and medical sciences; Brain; Brain - metabolism; General pharmacology; Imidazoles; Imidazoles - metabolism; Levocabastine; Life Sciences; Male; Medical sciences; Neurons and Cognition; Neurotensin receptor; Nonpeptide receptor antagonist; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Piperidines; Piperidines - metabolism; Rats; Rats, Sprague-Dawley; Receptor autoradiography; Receptors, Neurotensin; Receptors, Neurotensin - antagonists & inhibitors; Receptors, Neurotensin - metabolism; Tritium
• ISSN: 0014-2999; 1879-0712; 1879-0712; 0014-2999
• DOI: 10.1016/S0014-2999(97)01510-0

The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide antagonist of neurotensin receptors, [ 3 H ]SR 142948A (2-{[5-(2,6-dimethoxyphenyl)-1-(4-( N-(3-dimethylaminopropyl)- N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino}-adamantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [ 3 H ]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [ 3 H ]SR 142948A bound to an apparently homogeneous population of sites, with a K d of 3.5 nM and a B max value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [ 3 H ]neurotensin. [ 3 H ]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide receptor antagonist, SR 48692 (2-{[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino}-adamantane-2-carboxylic acid) and neurotensin. Saturation and competition studies in the presence or absence of the histamine H 1 receptor antagonist, levocabastine, revealed that [ 3 H ]SR 142948A bound with similar affinities to both the levocabastine-insensitive neurotensin NT 1 receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive neurotensin NT 2 receptors (80% of the receptors) ( K d=6.8 and 4.8 nM, respectively). The regional distribution of [ 3 H ]SR 142948A binding in the rat brain closely matched the distribution of [ 125 I ]neurotensin binding. In conclusion, these findings indicate that [ 3 H ]SR 142948A is a new potent antagonist radioligand which recognizes with high affinity both neurotensin NT 1 and NT 2 receptors and represents thus an excellent tool to study neurotensin receptors in the rat brain.