Neurokinin antagonist 1

Neurokinin 1 and 2 receptors are involved in PGE2- and citric acid-induced cough and ventilatory responses

Exposure to aerosolized citric acid (CA, 150 mM) and prostaglandin E2 (PGE2, 0.43 mM) for 10 min in guinea pigs reportedly produces the distinct cough patterns (Type I vs. II) and ventilatory responses (long-lasting hyperventilation vs. brief tachypnea) even though triggering the same cough numbers. Type I and II coughs are primarily mediated by activation of TRPV1 and EP3 receptors (a PGE2 receptor) of vagal C-fibers respectively. Substance P (SP) and neurokinin A (NKA) released by vagal pulmonary sensory fibers peripherally are capable of affecting CA-induced cough and ventilation via preferentially activating neurokinin 1 and 2 receptors (NK1R and NK2R) respectively. This study aimed to define the impacts of CA- and PGE2-exposure on pulmonary SP and NKA levels and the roles of NK1R and NK2R in modulating CA- and PGE2-evoked cough and ventilatory responses. In unanesthetized guinea pigs, we determined: (1) pulmonary SP and NKA contents induced by the CA- or PGE2-exposure; (2) effects of CP-99994 and SR-48968 (a NK1R and a NK2R antagonist respectively) given by intraperitoneal injection (IP) or aerosol inhalation (IH) on the CA- and PGE2-evoked cough and ventilatory responses; and (3) immunocytochemical expressions of NK1R/NK2R in vagal C-neurons labeled by TRPV1 or EP3 receptors. We found that CA- and PGE2-exposure evoked Type I and II cough respectively associated with different degrees of increases in pulmonary SP and NKA. Applications of CP-99994 and SR-48968 via IP and IH efficiently suppressed the cough responses to CA with less impact on the cough response to PGE2. These antagonists inhibited or blocked the ventilatory response to CA and caused hypoventilation in response to PGE2. Moreover, NK1R and NK2R were always co-expressed in vagal C-neurons labeled by TRPV1 or EP3 receptors. These results suggest that SP and NKA endogenously released by CA- and PGE2-exposure play important roles in generating the cough and ventilatory responses to CA and PGE2, at least in part, via activation of NK1R and NK2R expressed in vagal C-neurons (pulmonary C-neurons).

Novel triple neurokinin receptor antagonist CS-003 strongly inhibits neurokinin related responses

Neurokinins are known to induce neurogenic inflammation related to respiratory diseases, though there is little information on triple neurokinin receptor antagonists. The pharmacological properties of the novel triple neurokinin 1, 2 and 3 receptor antagonist [1-(2-[(2R)-(3,4-dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)morpholin-2-yl]ethyl)spiro[benzo[c]thiophene-1(3H),4'-piperidine]-(2S)-oxide hydrochloride] (CS-003) were evaluated in this study. The binding affinities of CS-003 were evaluated with human and guinea pig neurokinin receptors. As well, the in vivo antagonism of CS-003 against exogenous neurokinins and effects on capsaicin-induced and citric acid-induced responses were investigated in guinea pigs. CS-003 exhibited high affinities for human neurokinin 1, neurokinin 2 and neurokinin 3 receptors with Ki values (mean+/-S.E.M.) of 2.3+/-0.52, 0.54+/-0.11 and 0.74+/-0.17 nM, respectively, and for the guinea pig receptors with Ki values of 5.2+/-1.4, 0.47+/-0.075 and 0.71+/-0.27 nM, respectively. Competitive antagonism was indicated in a Schild analysis of substance P-, neurokinin A- and neurokinin B-induced inositol phosphate formation with pA2 values of 8.7, 9.4 and 9.5, respectively. CS-003 inhibited substance P-induced tracheal vascular hyperpermeability, neurokinin A- and neurokinin B-induced bronchoconstriction with ID50 values of 0.13, 0.040 and 0.063 mg/kg (i.v.), respectively. CS-003 also inhibited capsaicin-induced bronchoconstriction (ID50: 0.27 mg/kg, i.v.), which is caused by endogenous neurokinins. CS-003 significantly inhibited citric acid-induced coughs and the effect was greater than those of other selective neurokinin receptor antagonists. CS-003 is a potent antagonist of triple neurokinin receptors and may achieve the best therapeutic efficacy on respiratory diseases associated with neurokinins compared to selective neurokinin receptor antagonists.

Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivo

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.

The effect of inhaled FK224, a tachykinin NK-1 and NK-2 receptor antagonist, on neurokinin A-induced bronchoconstriction in asthmatics

The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.