NK1 receptor antagonist

In 1931, von Euler and Gaddum discovered substance P (SP) in horse brain and intestine. The substance showed strong vasodilatory effects and contractile activity on the rabbit gut. A great effort was put into purifying this substance from diverse mammalian tissue, but 30 years of research were without success. Nonmammalian peptides that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early 1960s. These peptides had a common C-terminal sequence, and were grouped together as tachykinins. In 1971, Chang managed to purify SP from horse intestine and identify its amino acid sequence; SP was then classified as a mammalian tachykinin. Later it became clear that SP was a neuropeptide that was common in the central and peripheral nervous system. In the mid 1980s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered. This led to further research, resulting in the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984, it was decided that the tachykinin receptors should be called tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor. Biological research that identified the many functions of tachykinins sparked interest in neurokinin receptor antagonists development. In 2003, the first NK1 receptor antagonist, aprepitant (Emend), received marketing approval from the U.S. Food and Drug Administration (FDA). == The neurokinin-1 receptor ==

Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino acid sequence Phe-X-Gly-Leu-Met-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp-Arg-Tyr, which is responsible for association with arrestin and, Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins. == Drug discovery and development ==

In 1991, three different groups researched different NK1 receptor antagonists by screening of chemical collections. Eastman Kodak and Sterling Winthrop discovered steroid series of tachykinin NK1 receptor antagonists that yielded some compounds but lacked sufficient affinity for the NK1 receptor, despite structure-activity relationship (SAR) studies that were performed. This series proved to have significant toxicity. Even though many derivatives of the steroid compounds have been synthesized, biological activity has not been improved. Rhône-Poulenc discovered the compound RP-67580, which has high affinity for the NK1 receptor in rats and mice, but not in humans. SAR studies that were performed in order to improve the selectivity for the human NK1 receptor resulted in the development of a compound called RPR-100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraines but then terminated, as was the case with other NK1 receptor antagonists that were tested for the same indication. Aprepitant was also believed to be effective in the treatment of depression. It entered phase III trials before the development for this indication was discontinued. Phe268 and Tyr287 have been proposed as possible contact points for both agonist and antagonist binding domains. It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane. In the development of MK-869, it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the TFMP group appeared to be especially important, and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group, can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue. The presence of an intramolecular face-to-face π–π interaction between two aromatic rings is a common feature of high affinity NK1 receptor antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally-restricted system, such as an eight-membered ring introduced into the naphthyridine ring. ==Future development==

Chemotherapy-induced emesis is a major problem in cancer treatment. A new compound, T-2328 (figure 7), a non-peptide antagonist of the tachykinin NK1 family, is studied for that purpose. T-2328 is administered intravenously, and treats both acute and delayed emesis. It is proposed to exert its anti-emetic effect through acting on brain NK1 receptors. T-2328 is very potent; the inhibition constant is of subnanomolar range and is 16 times lower than that of aprepitant. The inhibition is highly selective for NK1 receptors. The NK2 and NK3 receptors are also targets for novel classes of medications, and also show prominent antidepressive and anxiolytic effects. Studies showed that the inhibition constant (Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors. The affinity was also much lower for NK2 and NK3 receptors. Since tachykinins were discovered, they have been shown to possess biological activity in number of pathological and physiological systems. Nevertheless, the therapeutic potential of the tachykinin antagonists has not been fully understood. == See also ==