R.Michael Snider

CP-70,030 and CP-75,998: The first non-peptide antagonists of bombesin and gastrin releasing peptide

Abstract CP-70,030 and CP-75,998 were identified in a screening program as compounds able to displace [125I]-gastrin releasing peptide (GRP) from its rat brain receptor. We describe here the syntheses of these compounds and their characterization as bonafide GRP antagonists.

Preparation and radiolabelling of CP-96,345, the first non-peptide substance P antagonist

Abstract The preparation of CP-96,345, a potent, non-peptide Substance P antagonist, in both enantiomerically pure and radiolabelled forms is described. In addition, the absolute configuration of CP-96,345 was determined to be 2S,3S.

Nuclear variations of quinuclidine substance P antagonists: 2-diphenylmethyl-1-azabicyclo[3.2.2]nonan-3-amines

Abstract The synthesis and SAR of a series of 1-azabicyclo[3.2.2] analogues of the nonpeptide substance P antagonist CP-96,345 are described. The results demonstrate the sensitivity of the substance P receptor toward alterations in the nuclear structure of CP-96,345.

UK-73,093: A non-peptide neurotensin receptor antagonist

Abstract UK-73,093 was identified in a screening program as a compound able to displace [ 3 H]-neurotensin from its bovine brain receptor. We describe the discovery of this compound, species differences in receptor affinity and its characterization as a functional neurotensin antogonist in vitro and in vivo .

Chapter 11. The Role of Tachykinins in Pulmonary Disease

Publisher Summary This chapter discusses the possible role of neuropeptide substance P (SP) and related peptides in airway inflammatory conditions commonly known as asthma, bronchitis, and rhinitis. The biological effects of SP on nonneuronal tissues, which result directly from SP release following C-fiber activation, include stimulation of smooth muscle contraction, exocrine and endocrine gland secretion, and endothelial cell stimulation, leading to vasodilation, plasma extravasation, and neutrophil infiltration. The mammalian tachykinin peptides include SP, neurokinin A and B (NKA, NKB), and the N-terminally extended forms of NKA that include neuropeptide K (NPK) and neuropeptide (NPγ). Agonist activity is defined by the shared carboxy terminal domain (Phe-X-Gly-Leu-Met-NH 2 ), whereas the amino terminal domains determine receptor binding selectivity. These mammalian tachykinin polypeptides are derived from two distinct genes, the SP/NKA gene, and the NKB gene. Several tachykinin genes, with their multiple RNA splicing and post-translational processing mechanisms, generate substantial diversity in the tachykinin peptides that can be produced. The three mammalian tachykinin receptors have been cloned and shown to be the members of the G-protein coupled receptor family. They are coupled to inositol phospholipid metabolism and a rise in the cytosolic free calcium concentration. Each of the three receptors, which are termed neurokinin-1 (NK 1 ), NK 2 , and NK 3 , displays a moderate degree of selectivity for SP, NKA (also NPK and NPγ), and NKB, respectively. The vagal nerves contain afferent SP-immunoreactive nerve fibers from the lung. The cell bodies of these afferent C-fibers in the dorsal root ganglia (nodose ganglion) produce SP, 90% of which is transported into the peripheral vagal branches. Capsaicin-sensitive C-fibers are also known as polymodal nociceptive afferents, which means they are activated by thermal, mechanical, and chemical stimuli at their nerve endings. This is a key observation regarding the possible role of tachykinin-induced neurogenic inflammation in asthma and bronchitis. In addition to SP, C-fibers also contain NKA, NPK, and possibly NPγ, all very potent agonists at NK 2 receptors that can be coreleased in the lung upon afferent stimulation.

Synthesis of a nonpeptide carbon-11 labeled substance P antagonist for PET studies

CP 96,345 is a nonpeptide high affinity antagonist of the substance P (NK1) receptor. The radiosynthesis of [11C]CP 96,345 suitable for Positron Emission Tomography (PET) applications is described. [11C]CP 96,345 was prepared by O-methylation of a desmethyl precursor via in situ generation of its phenolate salt. The in vivo tissue distribution of [11C]CP 96,345 in guinea pigs (n = 2) at 5 and 30 min was determined. Uptake was low in brain (approximately 0.04% dose/g) and highest (approximately 1-2% dose/g) in the spleen and lungs. The present findings indicate that the use of [11C]CP 96,345 in PET might be more applicable to the study of substance P receptors in peripheral tissues involved with inflammatory disease and arthritis.

2-Aryl-1-azabicyclo[2.2.2]octanes as novel nonpeptide substance P antagonists

Abstract The synthesis and SAR of a series of 2-aryl-1-azabicyclo[2.2.2]octanes structurally related to the nonpeptide substance P antagonists CP-96,345 and CP-99,994 are described. The novel SAR observed at the 2-position in these derivatives represents a hybrid between that seen in the two previous series.