Disease relevance of TACR1

• The effect of the NK1 receptor antagonist CP-99,994 on emesis and c-fos protein induction by loperamide in the ferret [1].
• CP-96,345, [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine] a selective NK-1 tachykinin receptor blocker, inhibited substance P-induced hypotension in a dose-related manner [2].

High impact information on TACR1

• The antiemetic, pharmacokinetic, and metabolic profile of CP-99,994, a potent NK1 receptor antagonist, has been carefully evaluated [3].
• The marked reduction in behaviours associated with loperamide administration by CP-99,994 provides a preliminary indication that NK1 receptor antagonist (as represented by CP-99,994) may in the clinic have effects on behaviours induced by emetic agents in addition to their previously described effects on retching and vomiting [1].
• Substance P, the selective NK1 receptor agonist [Sar9,Met(O2)11]substance P and neurokinin A caused concentration-dependent production of 6-keto-PGF1 alpha; neurokinin A was least potent [4].
• 1. The effects of intracerebroventricular (i.c.v.) pretreatment with selective NK1 ((+/-)-CP 96,345), NK2a (MEN 10,207; MEN 10,376) and NK2b (R 396) tachykinin receptor antagonists on the cardiovascular and behavioural responses to i.c.v. substance P (SP) and neurokinin A (NKA) were studied in conscious rats [5].
• 1. We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium-denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues [6].

Biological context of TACR1

• These results indicate that there are at least two distinct types of tachykinin receptor binding sites in the canine gastrointestinal tract, one of which probably recognizes substance P and the other substance K as endogenous ligands [7].
• Vasorelaxation by casomokinin L, a derivative of beta-casomorphin and casoxin D, is mediated by NK1 receptor [8].

Anatomical context of TACR1

• To determine precisely the site of this action, we microinjected GR205171, an NK1 receptor antagonist, into the left medulla oblongata in decerebrate paralyzed dogs [9].
• The tachykinin NK1 receptor antagonist GR205171 prevents vagal stimulation-induced retching but not neuronal transmission from emetic vagal afferents to solitary nucleus neurons in dogs [10].
• NK-1 binding sites characterized in rat brain homogenates appear to be identical with those present on the dog carotid artery, a preparation known to possess exclusively the NK-1 receptor type [11].
• 125I-BH[Sar9, Met(O2)11]-SP, a new selective ligand for the NK-1 receptor in the central nervous system [11].
• The variable effects, potencies, and mechanisms of action observed in this study suggest the presence of specific tachykinin receptor subtypes in the gastroesophageal junction [12].

Associations of TACR1 with chemical compounds

• The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P [13].
• The behavioural effects of the selective NK-3 tachykinin receptor agonist senktide were studied following intracisternal and subcutaneous administration in rodents [14].
• The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P [13].
• 1. The selective NK1 receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli [15].
• In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events [16].

References