Neurokinin-receptor antagonists: pharmacological tools and therapeutic drugs.

The mammalian tachykinins (substance P, neurokinin A, and neurokinin B) are widely distributed throughout the central and peripheral nervous systems, where they act as neurotransmitters or neuromodulators. Historically, the tachykinins have been implicated in a wide variety of biological actions such as pain transmission, neurogenic inflammation, smooth muscle contraction, vasodilation, secretion, and activation of the immune system. Their effects are mediated via specific G-protein-coupled receptors (NK1, NK2, and NK3 receptors). The development of nonpeptide receptor antagonists revealed species differences in neurokinin-receptor pharmacology, and the recent cloning of human neurokinin receptors has led to development of compounds with optimized affinity for the human target receptor. The neurokinin-receptor antagonists have been used in preclinical experiments to confirm the physiological roles of the tachykinins. Importantly, it is now recognised that these agents can inhibit the actions of tachykinins released from peripheral nerves, and for the NK1-receptor antagonists (the most widely studied class of neurokinin-receptor antagonists) central sites of action have also been demonstrated. These studies support the development of neurokinin-receptor antagonists as potentially exploitable drug therapies in humans, particularly in the treatment of pain and emesis.