A Potent Nonpeptide Antagonist of the Substance P (NK$_1$) Receptor

• Published in: Science (American Association for the Advancement of Science) 1991-01, Vol.251 (4992), p.435-437
• Main Authors: Snider, R. Michael, Constantine, Jay W., Lowe, John A., Longo, Kelly P., Lebel, Wesley S., Woody, Heidi A., Drozda, Susan E., Desai, Manoj C., Vinick, Frederic J., Spencer, Robin W., Hess, Hans-Jürgen
• Format: Article
• Language: English
• Subjects: 550201 - Biochemistry- Tracer Techniques; Agonists; ANIMALS; Antagonists; ARTERIES; BASIC BIOLOGICAL SCIENCES; Binding, Competitive; BIOCHEMICAL REACTION KINETICS; Biochemistry; Biological and medical sciences; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; BLOOD VESSELS; BODY; CARDIOVASCULAR SYSTEM; CAROTID ARTERIES; Carotid Arteries - drug effects; Cattle; Cell receptors; Cell structures and functions; DOGS; Enantiomers; Enzymes; Fundamental and applied biological sciences. Psychology; GLANDS; HYDROGEN COMPOUNDS; INHIBITION; ISOTOPE APPLICATIONS; KINETICS; KININS; LIGANDS; MAMMALS; Medical research; MEMBRANE PROTEINS; Molecular and cellular biology; Molecular Structure; Molecules; Muscle Contraction - drug effects; Muscle Relaxation - drug effects; Neuropeptide receptors; Norepinephrine; ORGANIC COMPOUNDS; ORGANS; PEPTIDES; POLYPEPTIDES; PROTEINS; Rabbits; RATS; REACTION KINETICS; RECEPTORS; Receptors, Neurokinin-1; Receptors, Neurotransmitter - antagonists & inhibitors; RODENTS; SALIVARY GLANDS; Salivation; Salivation - drug effects; Stereoisomerism; Substance P; Substance P - metabolism; Substance P - pharmacology; Tachykinins; TRACER TECHNIQUES; TRITIUM COMPOUNDS; Ungulates; VERTEBRATES
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1703323

CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2] octan-3-amine] is a potent nonpeptide antagonist of the substance P (NK$_1$) receptor. CP-96,345 inhibited $^3$H-labeled substance P binding and was a classical competitive antagonist in the NK$_1$ monoreceptor dog carotid artery preparation. CP-96,345 inhibited substance P-induced salivation in the rat, a classical in vivo bioassay, but did not inhibit NK$_2$, NK$_3$, or numerous other receptors; it is thus a selective NK$_1$ antagonist. This compound may prove to be a powerful tool for investigation of the physiological properties of substance P and exploration of its role in diseases.