the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. When NK1 receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the arachidonic acid mobilization via phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase. It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, it is known to sensitize neutrophils and enhance dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine and GABA. It is also known to secrete catecholamines and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E2 and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output. In combination therapy, NK1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK1 receptor antagonists. NK1 receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT3 antagonist treatments. It has been reported that centrally-acting NK1 receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms. Clinical significance This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants. It is also a potential treatment for alcoholism and opioid addiction. In addition, it has been identified as a candidate in the etiology of bipolar disorder. Finally NK1R antagonists may also have a role as novel antiemetics and hypnotics. Ligands Many selective ligands for NK1 are now available, several of which have gone into clinical use as antiemetics. Agonists GR-73632 - potent and selective agonist, EC50 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6 Antagonists Aprepitant Casopitant Elinzanetant Ezlopitant Fosaprepitant Lanepitant Maropitant Vestipitant L-733,060 L-741,671 L-742,694 RP-67580 - potent and selective antagonist, Ki 2.9nM, (3aR,7aR)-Octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl ]-7,7-diphenyl-4H-isoindol, CAS# 135911-02-3 RPR-100,893 CP-96345 CP-99994 GR-205,171 TAK-637 T-2328 See also NK1 receptor antagonist Tachykinin