The goal of this proposal is to synthesize irreversible non-peptide antagonists of the neurokinin-1 (NK-1) receptor. The irreversible ligands will be prepared from CP-99,994 and a benzyloxy analog of CP-99,994. Both lead compounds are selective, high affinity, non-competitive, reversible antagonists of the NK-1 receptor. Three isothiocyanate derivatives, 3 bromoacetamide derivatives, and two azido photoaffinity derivatives of the lea compounds will be prepared. It is expected that these derivatized compounds will form a covalent link with the receptor while similar but non-reactive derivatives should retain reversibility. The synthesized NK-l receptor ligands will be tested for their antagonist potency, selectivity, and reversibility on smooth muscle from guinea pig trachea and ileum. Ligand binding studies will b performed on CHO cells transfected with human/rat NK-1 receptors.
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