Development of NK-2 selective antagonists

1 The aim of this study was the pharmacological characterization of tachykinin NKI and NK2 receptors mediating contraction in the circular muscle of the guinea-pig ileum and proximal colon. The action of substance P (SP), neurokinin A (NKA) and of the synthetic agonists [ Furthermore, an intraspecies heterogeneity of the NK2 receptor in the circular muscle of the guinea-pig ileum and colon is suggested.

Section: Introductionmentioning

confidence: 99%

Comparison of tachykinin NK₁ and NK₂ receptors in the circular muscle of the guinea‐pig ileum and proximal colon

Maggi

Patacchini

Meini

et al. 1994

“…The working hypothesis was that both SP and NKA contribute to the overall response to capsaicin and that both NK1 and NK2 receptors may be involved. With this aim, we first evaluated the effect of low concentrations of SP and NKA alone and in combination in comparison with the response to capsaicin and then assessed the effect of spantide, a SP antagonist of the first generation endowed with some selectivity for the NK1 receptor (Leander et al, 1981;Buck & Shatzer, 1988) and of some newly developed selective antagonists which discriminate between NK1 and NK2 receptors Williams et al, 1988;Maggi et al, 1990a). The effects of bombesin and P2X purinoceptor desensitization by the stable ATP analogue ac,f8-methylene ATP were also investigated.…”

Section: Introductionmentioning

confidence: 99%

Tachykinin antagonists and capsaicin‐induced contraction of the rat isolated urinary bladder: evidence for tachykinin‐mediated cotransmission

Maggi

Patacchini

Santicioli

et al. 1991

1 The possible involvement of tachykinins (TKs) in the contraction produced by capsaicin in the rat isolated urinary bladder was addressed on the hypothesis that co-release of substance P (SP) and neurokinin A (NKA) occurs from sensory nerve terminals. 2 A low concentration of SP (30 nM) produced a rapid contraction which faded to baseline within 10min. A low concentration of NKA (10nM) produced a slowly developing contraction which was still evident at 10min. Capsaicin (1 pM) produced a rapid phasic response and a tonic response (late response to capsaicin). Co-administration of SP and NKA mimicked the response to capsaicin more than each TK alone. 3 Fading of the response to SP was not caused by receptor desensitization and was partially prevented by peptidase inhibitors.4 Spantide (3pM) selectively antagonized the SP-induced contraction while L-659,877 (3-lOpM) or MEN 10,376 (10-30pM) which are NK2 receptor selective antagonists selectively blocked the response to NKA.Co-administration of spantide and L-659,877 inhibited the response to both SP and NKA by an amount not greater than that produced by each antagonist alone. 5 Spantide selectively reduced the peak response to capsaicin, while leaving the late response unaffected.L-659,877 (3 pM) and MEN 10,376 (10pM) selectively inhibited the late response to capsaicin while, at higher concentrations, also reduced the peak response to capsaicin. Co-administration of spantide and L-659,877 reduced the peak response to capsaicin more than that produced by each antagonist alone. 6 Bombesin (10nM) produced a tonic contraction similar to that induced by NKA. The response to bombesin was not affected by spantide, L-659,877 or MEN 10,376. 7 P2. purinoceptor desensitization by repeated administration of a,fl-methylene ATP depressed the twitch response to electrical stimulation of postganglionic nerves but did not affect the peak or the late response to capsaicin. 8 We conclude that multiple TKs are coreleased by capsaicin in the rat bladder and mediate the capsaicin-induced contraction by activating both NKI and NK2 receptors. Endogenous TK with preferential affinity for the NK, receptor (putatively SP) are selectively involved in the peak response to capsaicin while endogenous TK with preferential affinity for the NK2 receptor (putatively NKA) are selectively involved in the late response to capsaicin and partly contribute to the peak response. These findings provide pharmacological evidence for tachykinin-mediated cotransmission in the rat urinary bladder. ATP is unlikely to be involved in the efferent function of capsaicin-sensitive sensory nerves in the rat bladder.

“…Novel neurokinin receptor antagonists include the NK, selective antagonist Leu'0,Trp1 1]-SP(,1 1); GR71251 Ward et al, 1990), and the NK2 selective antagonist cyclo(Gln,Trp,Phe,Gly,Leu,Met) (L659,877;McKnight et al, 1988;Williams et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

Novel selective agonists and antagonists confirm neurokinin NK₁ receptors in guinea‐pig vas deferens

Hall

Morton

1991

1 This study investigated the recognition characteristics of neurokinin receptors mediating potentiation of the contractile response to field stimulation in the guinea-pig vas deferens.2 A predominant NK, receptor population is strongly suggested by the relative activities of the common naturally-occurring tachykinin agonists, which fall within less than one order of magnitude. This conclusion is supported by the relative activities of the synthetic NK, selective agonists substance P methyl ester, [Glp6,L-Pro9]-SP(6, 1) and 6-aminovaleryl-[L-Pro9,N-MeLeul']-SP(7 ,l) (GR73632) which were 0.78, 9.3 and 120 as active as substance P, respectively. Furthermore, the NK2 selective agonist [Lys3, Gly8,-R-y-lactam-Leu9]-NKA(3,0) (GR64349) was active only at the highest concentrations tested Trpl 1]-SP(1-1) (GR71251) did not produce agonist-dependent pKB estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pKB of 7.58 + 0.13 for the four agonists of differing subtype selectivity tested (GR73632, GR64349, substance P methyl ester and neurokinin B). This estimate is similar to that we obtained for NK1-mediated (substance P methyl ester) contraction in the guinea-pig ileum preparation (pKB= 7.86 + 0.05).5 Tachykinin action appears not to depend on release of a number of intermediary mediators including acetylcholine, histamine or cyclo-oxygenase products, nor to involve interaction with neuronal mechanisms including a2-adrenoceptor feedback, noradrenergic Uptake-I or opioid-release, since antagonism or inhibition of these mechanisms did not modify responses to tachykinins. 6 We conclude that tachykinin action in the field-stimulated guinea-pig vas deferens preparation is mediated through interaction with a predominant neurokinin NK, receptor population and this preparation can therefore be used to study NK, modulation of sympathetic neurotransmission.