S.J. Ireland
University of Hertfordshire
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by S.J. Ireland.
British Journal of Pharmacology | 1988
A. Butler; J.M. Hill; S.J. Ireland; Christopher C. Jordan
1 This paper describes the pharmacology of the novel 5‐hydroxytryptamine3 (5‐HT3) receptor antagonist GR38032F. 2 On the isolated vagus nerve and superior cervical ganglion of the rat, R,S‐GR38032F behaved as a reversible competitive antagonist of 5‐HT‐induced depolarization with pKB values of 8.61 ± 0.08 (n = 19) and 8.13 ± 0.07 (n = 16), respectively. The resolved R‐ and S‐isomers of GR38032F were approximately equipotent as 5‐HT antagonists on the rat vagus nerve: the pKB values were 8.95 ± 0.05 (n = 16) and 8.63 ± 0.08 (n = 17), respectively. R,S‐GR38032F was also an effective antagonist of 5‐HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 ±0.14 (n = 4). 3 On the rabbit isolated heart, low concentrations of R,S‐GR38032F (3 × −1011 −1 × 10‐9 m) antagonized the positive chronotropic effect of 5‐HT and 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4 On the longitudinal smooth muscle of the guinea‐pig ileum, R,S‐GR38032F caused concentration‐dependent parallel rightward displacement of the 2‐methyl‐5‐HT concentration‐contraction response curve; in contrast, a portion of the response to 5‐HT appeared resistant to R,S‐GR38032F. pKB values estimated from the effects of the compound against 2‐methyl‐5‐HT or the inhibitable portion of the response to 5‐HT were 7.31 ± 0.06 (n = 8) and 7.33 ± 0.13 (n = 8), respectively. Against 2‐methyl‐5‐HT, R‐GR38032F seemed more potent (pKB 7.20 ± 0.10; n = 6) than S‐GR38032F (pKB 6.30 ± 0.05; n = 6). 5 R,S‐GR38032F is highly selective for 5‐HT3 receptors, and at concentrations of 3 × 10−6‐3 × 10−5m, had negligible agonist or antagonist activity on other 5‐HT or non‐5‐HT receptor‐containing tissues on which it was tested. 6 The potency and duration of action of R,S‐GR38032F in blocking 5‐HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5‐HT or 2‐methyl‐5‐HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S‐GR38032F against 2‐methyl‐5‐HT (100 μg kg−1) was 0.4 (95% confidence limits 0.18–0.87) μg kg−1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0–22.0) μg kg−1 (n = 8–10 per dose level). R,S‐GR38032F was similarly effective in the anaesthetized cat. 7 The present results are discussed with reference to the postulated existence of subtypes of the 5‐HT3 receptor.
British Journal of Pharmacology | 1991
I.J.M. Beresford; Philip J. Birch; R.M. Hagan; S.J. Ireland
The affinity of the non‐peptide antagonist CP‐96,345 for tachykinin NK1 receptors has been estimated in a range of species by use of both radioligand binding and functional assays. CP‐96,345 was 30–120 fold less active at NK1 receptors in rat and mouse than in the other species examined, including man. These results demonstrate the existence of species variations in NK1 receptors.
British Journal of Pharmacology | 1990
A. Butler; C.J. Elswood; J. Burridge; S.J. Ireland; K.T. Bunce; G.J. Kilpatrick
1 The pharmacological characterization of the 5‐HT3 receptors in guinea‐pig isolated tissues is described. The tissues used were ileum (longitudinal muscle‐myenteric plexus), colon and vagus nerve. The guinea‐pig isolated colon is a novel preparation. 2 In the guinea‐pig isolated ileum, 5‐hydroxytryptamine (5‐HT, 1 × 10−8−3 × 10−5 m) and the selective 5‐HT3 receptor agonist 2‐methyl‐5‐HT (3 × 10−7−1 × 10−4 m) caused concentration‐related contractions. The 5‐HT concentration‐response curve was biphasic whilst the 2‐methyl‐5‐HT curve was monophasic. The EC50 value for the low potency portion of the 5‐HT curve was 4.1 × 10−6 m. The EC50 for 2‐methyl‐5‐HT was 1.23 × 10−5 m. Selective 5‐HT3 receptor antagonists caused rightward shifts of the 2‐methyl‐5‐HT curve and the lower potency portion of the 5‐HT curve. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) antagonized the responses to 5‐HT or 2‐methyl‐5‐HT. 3 In the guinea‐pig isolated colon, 5‐HT (3 × 10−7−3 × 10−5 m; EC50 2.4 × 10−6 m) caused contractions which were mimicked by 2‐methyl‐5‐HT (1 × 10−6−1 × 10−4 m; EC50 7.2 × 10−6 m). Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) had any effect on responses to 5‐HT or 2‐methyl‐5‐HT. 4 In the guinea‐pig isolated vagus nerve, 5‐HT (1 × 10−6−3 × 10−4 m) and 2‐methyl‐5‐HT (1 × 10−5−1 × 10−3 m; EC50 7.6 × 10−5 m) caused depolarizations; at higher concentrations there were afterhyperpolarizations. The maximum response to 2‐methyl‐5‐HT was less than half that to 5‐HT. Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Antagonists at other 5‐HT receptors (ketanserin, 1 × 10−5 m and methysergide, 1 × 10−6 m) had no effect. 5 The estimated affinity values of 5‐HT3 receptor antagonists correlated well between the three models. Phenylbiguanide was inactive as an agonist or antagonist (up to 1 × 10−4 m) in each preparation. 6 Comparisons with antagonist affinity values obtained in the rat isolated vagus nerve revealed marked differences. Antagonists were generally more potent on the rat isolated vagus nerve, although the differences varied considerably between antagonists. 7 The results are discussed in terms of species‐related receptor differences.
Neuropeptides | 1991
R.M. Hagan; S.J. Ireland; Christopher C. Jordan; I.J.M. Beresford; M.J. Deal; P. Ward
The pharmacological profiles of two novel neurokinin agonists have been investigated. delta Ava[L-Pro9,N-MeLeu10]SP(7-11) (GR73632) and [Lys3,Gly8-R-gamma-lactam-Leu9] NKA(3-10) (GR64349) are potent and selective agonists at NK-1 and NK-2 receptors respectively. In the guinea-pig isolated trachea preparation, contractions induced by these agonists were largely unaffected by inclusion of peptidase inhibitors in the bathing medium, indicating that these agonists are resistant to metabolism by peptidases. In the anaesthetised guinea-pig, both agonists were more potent bronchoconstrictor agents than either NKA or the SP analogue, SP methylester. In the anaesthetised rat, the NK-1 agonist, GR73632 was more potent than SP, NKA or NKB at causing the histamine-independent extravasation of plasma proteins into the skin after intradermal administration. The NK-2 agonist, GR64349 and the NK-3 agonist, senktide were without significant effect in this model. These agonists are useful tools for characterizing neurokinin receptor-mediated actions both in vitro and in vivo.
British Journal of Pharmacology | 1991
S.J. Ireland; F. Bailey; A. Cook; R.M. Hagan; Christopher C. Jordan; M.L. Stephens‐Smith
1 The classification of tachykinin receptors in the guinea‐pig trachea has been investigated. This was of interest because, from previous studies, it was not clear whether the guinea‐pig trachea contains either a mixture of NK1 and NK2 receptors or, alternatively, a single type of novel tachykinin receptor. 2 In the present study, the guinea‐pig trachea was contracted by tachykinin agonists selective for NK1 receptors (substance P methylester (SPOMe) and GR73632) or NK2 receptors (GR64349) but not NK3 receptors (senktide). 3 Against SPOMe and GR73632, the NK1 antagonist, GR71251, behaved as a reversible competitive antagonist having apparent affinity (pKB 7.05 vs SPOMe) consistent with action at NK1 receptors. GR71251 (3 μm) did not antagonize responses to GR64349. 4 The NK2 antagonists L‐659,877 and Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH2 (R396) antagonized GR64349 although only R396 appeared to behave competitively (pKB 5.73). Neither L‐659,877 (30 μm) nor R396 (30 μm) blocked responses to SPOMe. 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.
Neuroscience | 1992
I.J.M. Beresford; S.J. Ireland; J. Stables; R.M. Hagan
The distribution and characteristics of [125I]Bolton Hunter-eledoisin binding sites in rat lumbar spinal cord were studied during postnatal development by in vitro receptor autoradiography. At three, six and 10 days of age, specific [125I]eledoisin binding was distributed throughout the dorsal and ventral horns of the spinal cord. In contrast, from day 24 onwards, specific binding of [125I]eledoisin was confined to superficial layers of the dorsal horn, with negligible amounts of specific binding in the ventral horn. [125I]Eledoisin binding to neonatal (three day) and adult (eight to 12 weeks) spinal cord sections was characterized using tachykinin agonists. In both dorsal and ventral horns of neonatal spinal cord, the rank order of potency of agonists indicated that the majority (64%) of specific [125I]eledoisin binding was to neurokinin-3 binding sites. The identity of the non-neurokinin-3 sites labelled by [125I]eledoisin remains to be determined. In adult rat spinal cord, [125I]eledoisin appeared to bind exclusively to neurokinin-3 binding sites. These results suggest that major changes take place in the localization of neurokinin-3 receptors during postnatal ontogeny of the rat spinal cord. These changes may reflect an important role for tachykinins in neuronal plasticity of the developing spinal cord.
Bioorganic & Medicinal Chemistry Letters | 1993
P.W. Smith; Andrew B. McElroy; J.M. Pritchard; M.j. Deal; G.B. Ewan; R.M. Hagan; S.J. Ireland; D. Ball; I. Beresford; R. Sheldrick; Christopher C. Jordan; Peter Ward
Abstract A deletion - optimization strategy based on an initial heptapeptide lead structure 1 led to potent and selective neurokinin NK2 antagonists 5 (pKB=9.3) and 9 (pKB=7.9) of substantially reduced molecular size. Tetrapeptide 5 (0.1 μmol/Kg i.v.) potently inhibits NK2 agonist-induced bronchoconstriction in guinea-pigs. Whilst less potent than 5 in vivo, the dipeptoid 9 (5 μmol/Kg i.v.) had a significantly longer biological half-life (> 2 h), and provides a potential lead towards non-peptide analogues.
Journal of Medicinal Chemistry | 1990
Peter Ward; G. B. Ewan; Christopher C. Jordan; S.J. Ireland; R.M. Hagan; J. R. Brown
European Journal of Pharmacology | 1987
R.M. Hagan; Arthur Butler; Julia M. Hill; Christopher C. Jordan; S.J. Ireland
Journal of Medicinal Chemistry | 1992
Andrew B. McElroy; Stephen P. Clegg; Martyn J. Deal; George B. Ewan; R.M. Hagan; S.J. Ireland; Christopher C. Jordan; Barry Porter; Barry C. Ross