Potent and highly selective neurokinin antagonists

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.

Section: Neurokinin Receptor Subtypes; Antagonist Studiessupporting

confidence: 90%

Section: Neurokinin Receptor Subtypes; Antagonist Studiesmentioning

confidence: 99%

See 1 more Smart Citation

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

Hall

Morton

1991

“…GR71251 behaved as a reversible competitive antagonist of SPOMe-induced contraction with apparent affinity (pKB 7.05) comparable with that exhibited at NK1 receptors in other tissues (7.72, guinea-pig ileum; 7.06, rabbit aorta; Hagan et al, 1990), but quite different from that measured at NK2 receptors (pKB 4.8; Ward et al, 1990). The rela.-tively small differences in apparent affinity of GR71251 in the three NK1 receptor containing preparations remains to be explained, as does the observation that in guinea-pig trachea, another NK,antagonist,169, is inactive against SPOMe (Maguire et al, 1989) despite having a pA2 of 7.0 against NK, receptor-mediated contraction of the guinea-pig ileum .…”

Section: Discussionmentioning

confidence: 70%

Receptors mediating tachykinin‐induced contractile responses in guinea‐pig trachea

Ireland

Bailey

Cook

et al. 1991

1 The classification of tachykinin receptors in the guinea-pig trachea has been investigated. This 5 For L-659,877 and R396, comparison was made between activity in guinea-pig trachea and in preparations known to contain tachykinin receptors predominantly of the NK2 type. In the rabbit trachea, both L-659,877 and R396 had effects similar to those in guinea-pig trachea. In contrast, in the rat colon muscularis mucosae, both L-659,877 and R396 appeared to behave competitively with pKB values against GR64349 of 7.83 and 6.90 respectively. 6 It is concluded that in guinea-pig trachea, contractile responses can be induced by activation of both NK1 and NK2 receptors. The present data are discussed with reference to the proposed existence of subtypes of the NK2 receptor.

“…The problems associated with classification of receptors only on the basis of differences in rank order of potency of agonists are well known (Kenakin, 1984;Watson, 1984). Important progress has been made recently in the discovery of both peptide (Ward et al, 1990) and non-peptide antagonists (Snider et al, 1991) Ltd, 1991 Some of these findings have been the subject of a preliminary communication (Bantin & Kingman) and of homogenates of urinary bladder from 80-160g male Golden Syrian hamsters (Intersimian Ltd) were as described previously (Lee et al, 1986;Foster & Tridgett, 1988); these were stored in a concentration of approximately 10mg protein ml-at -80'C prior to use.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors

McKnight

Maguire

Elliott

et al. 1991

1 The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively 4 The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam-containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.