Tachykinin Antagonists

The discovery of nonpeptide antagonists of the tachykinin peptides substance P, neurokinin A, and neurokinin B has greatly accelerated pharmacological characterization of the role of these peptides and their receptors (NK-1, NK-2, and NK-3) in the central nervous system (CNS). The extensive structural diversity of the nonpeptide tachykinin antagonists offers considerable potential for therapeutic agents targeting this system, and includes NK-1 antagonists such as: I. the quinuclidine amines (CP-96,345) and related ethers, 2. the piperidine amines (CP-99,994) and related ethers and acyclic variants, 3. the isoindolines such as RP 67,580 and RPR 100,893, 4. the 2-benzylpiperidines CGP-47,899 and CGP 49,823, 5. the peptide-derived FK-888, and 6. SR-140,333, as well as NK-2 antagonists such as SR-48,968, and GR-159,897, and NK-3 antagonists such as PD- 157,652 and SR-142,801. Important new pharmacological insights facilitated by these compounds indicate a role for tachykinin peptides in control of dopamine function in the CNS, emesis, pain, and neurogenic inflammation. These compounds have also enabled characterization of the nonpeptide antagonist binding site on the NK-1 receptor, providing insight on the mechanism of receptor antagonism to help in the design of new compounds. Hence the nonpeptide tachykinin antagonists continue to play an important role in characterizing biochemical, pharmacological, and potential therapeutic aspects of the tachykinin peptides.