Christopher C. Jordan
University of Hertfordshire
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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.
European Journal of Pharmacology | 1993
Chaz Bountra; K.T. Bunce; Timothy James GlaxoSmithKline Dale; Christopher J. Gardner; Christopher C. Jordan; David J. Twissell; Peter Ward
In the ferret, 5-HT3 receptor antagonists are effective in controlling emesis produced by cytotoxic agents or radiation. To investigate the possibility that substance P has a role, as well as 5-HT, in the emetic reflex pathway, we have examined the anti-emetic effects of a NK1 receptor antagonist (racemic CP-99,994) in the ferret. Racemic CP-99,994 was effective against a range of emetogens, comprising cytotoxic drugs, radiation, morphine, ipecacuanha and copper sulphate.
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 | 1990
R.M. Hagan; B.J. Jones; Christopher C. Jordan
1 The effects of 5‐hydroxytryptamine3 (5‐HT3) receptor antagonists on the behavioural hyperactivity response which results from injection of the neurokinin receptor agonist [pGlu5, MePhe8, Sar9]‐substance P (5–11) (DiMe‐C7) into the ventral tegmental area (VTA) of the rat midbrain have been determined. 2 Subcutaneous administration of ondansetron (GR38032) (0.001–0.3 mg kg−1), GR65630 (0.01 mg kg−1), ICS 205–930 (0.1 mg kg−1) and MDL 72222 (0.1 mg kg−1), inhibited the DiMe‐C7‐induced hyperactivity response. 3 The effects of ondansetron on DiMe‐C7‐induced changes in dopamine and 5‐HT metabolism in discrete areas of rat forebrain were studied in order to investigate further the possible mechanism of action of 5‐HT3 antagonists in modifying mesolimbic dopaminergic systems. 4 Intra‐VTA administration of DiMe‐C7 increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens, olfactory tubercules and right amygdala, indicating increased mesolimbic dopamine metabolism. DOPAC levels were not significantly increased in the frontal cortex, left amygdala or striatum. Dopamine levels were not altered in any of these brain areas. DiMe‐C7 also increased 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the amygdala but this was only statistically significant in the right amygdala. 5‐HT levels were not changed significantly by DiMe‐C7 treatment. 5 In control rats, pretreatment with ondansetron (0.1 mg kg−1) had no effect on the levels of dopamine, 5‐HT or their metabolites, but in rats given DiMe‐C7, ondansetron significantly inhibited the increase in DOPAC levels in the nucleus accumbens. 6 These results are in agreement with the proposed facilitatory role of 5‐HT3 receptor activation on mesolimbic dopaminergic transmission, and suggest that 5‐HT3 antagonists may have important therapeutic indications for the treatment of CNS disorders in which mesolimbic dopamine systems are perturbed.
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.
British Journal of Pharmacology | 1991
G. A. Higgins; Christopher C. Jordan; M. Skingle
1 The effects of various 5‐hydroxytryptamine (5‐HT) receptor agonists were examined following unilateral infusion into the substantia nigra (SN) of the guinea‐pig. 2 The 5‐HT1 receptor agonists, 5‐carboxamidotryptamine (5‐CT) (2–25 μg), sumatriptan (10–25 μg) and RU24969 (25 μg) all induced a marked contralateral rotation. In contrast, the selective 5‐HT1A receptor agonist 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH DPAT, 10–25 μg) produced only a very small response, whilst the selective 5‐HT1C/5‐HT2 receptor agonist (±)‐1‐(4‐iodo‐2,5‐dimethoxyphenyl)‐2‐aminopropane hydrochloride ((±)‐DOI) (25 μg) and the 5‐HT3 receptor agonist, 2‐methyl 5‐HT (2‐Me5‐HT, 25 μg) were without effect. 3 The contralateral rotation induced by 5‐CT (10 μg) was attenuated following pretreatment with the non‐selective 5‐HT1/5‐HT2 receptor antagonists methiothepin (1 mg kg−1, s.c.) and metergoline (5–10 mg kg−1, s.c.) but not the 5‐HT1C/5‐HT2 antagonist ritanserin (1 mg kg−1, s.c.) or the 5‐HT3 antagonist, ondansetron (0.5 mg kg−1, s.c). An involvement of dopaminergic systems in the rotational response to 5‐CT was implied by the antagonism of 5‐CT‐induced rotation by haloperidol (0.3 mg kg−1, s.c). 4 At doses lower than those required to produce contralateral rotation, 5‐CT (0.08–0.4 μg) and sumatriptan (2 μg) induced a small, but nonetheless consistent, ipsilateral rotation. 5 The data with agonists and antagonists taken together suggest that 5‐CT‐induced contralateral rotation may be mediated by 5‐HT1D receptor activation but definitive classification of the receptor will not be possible until selective 5‐HT1D‐antagonists become available. This may therefore represent the first model to study this receptor subtype in vivo.
Trends in Neurosciences | 1986
J.R. Brown; J.C. Hunter; Christopher C. Jordan; M.B. Tyers; P. Ward; A.R. Whittington
In recent years, a wide range of peptides have become available from commercial suppliers. Analyses of tachykinin-related peptides from several suppliers have detected a disturbing number of inadequacies in quality control. Most strikingly, five peptides have been supplied to us as incorrect sequences, and in addition, we have found considerable variation in absolute peptide content per mg of material supplied. Our experience with radiolabelled substance P has also cast doubt on the reliability of existing quality control arrangements. In this article, we draw attention to the possible pitfalls that await users of peptides and we make recommendations for the improvement of quality control in commercial peptide houses.
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.
Neuropeptides | 1989
Marcus Rattray; Christopher C. Jordan; J. de Belleroche
The relationship between CCK- and opioid-activated systems in antinociception is not clear. The effects of morphine, naloxone and naltrexone on the antinociceptive effect of systemically administered caerulein was determined using the paw pressure test in the rat. Caerulein treatment significantly increased paw pressure threshold with an ED50 of 30 micrograms/kg (22.2 nmol/kg) and was considerably more potent than morphine in this respect (ED50 of 882 nmol/kg). The opioid antagonists naloxone and naltrexone were found to potentiate the antinociceptive effect of caerulein (30 micrograms/kg) whilst abolishing the effect of morphine at doses of 3 micrograms/kg and above. Co-administration of caerulein (30 micrograms/kg) with low doses of morphine, normally ineffective in the paw pressure test, abolished caerulein-induced antinociception. However the effects of antinociceptive doses of morphine were depressed by caerulein (30 micrograms/kg), showing a mutual antagonism between caerulein and opioid activated effects. In contrast to these observations, morphine pre-injection (3h before testing) was found to significantly potentiate caerulein-induced antinociception revealing a differential interaction between opioid and CCK systems at different time points. The results indicate that CCK and opioids produce antinociception by separate, yet overlapping mechanisms.
Journal of Medicinal Chemistry | 1990
Peter Ward; G. B. Ewan; Christopher C. Jordan; S.J. Ireland; R.M. Hagan; J. R. Brown