CP-99994 (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine is a selective tachykinin NK(1) receptor antagonist that inhibits cough in guinea pigs and cats. This study examined the antitussive ...effects of CP-99994 in dogs produced by mechanical stimulation of the intrathoracic trachea. CP-99994 (10 mg/kg, p.o.) inhibited cough frequency by 52% at 2 h, 31% at 6 h and by 21% at 24 h. Cough amplitude was inhibited by 45% at 6 h but unchanged at 2 and 24 h after CP-99994. Plasma levels of CP-99994 were highest at 2 h (75+/-26 ng/ml) and fell to 22+/-6 ng/ml at 6 h. These results demonstrate antitussive activity of CP-99994 in dogs at a dose proven to antagonize tachykinin NK(1) receptors in this species.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Type 1 diabetes is a complex disorder with interaction of both genetic and environmental factors. One of the loci, IDDM4, has been mapped to chromosome 11q13, with evidence of association to two ...markers, D11S1917 and H0570polyA. To identify putative candidate genes for IDDM4, we have constructed a 400-kb clone contig in this region and sequenced the clones. We have also sequenced the orthologous DNA from mouse. Previously, we identified a cDNA for the low-density lipoprotein receptor-related protein 5 gene (LRP5) 3 kb distal to H0570polyA. We have now determined the exon–intron structure of this gene. Detailed sequence analysis has identified a further three genes in this region: the CGI-85 gene (previously identified by W.-C. Lin) and two novel genes, C11orf24 and C11orf23. The C11orf24 gene has no known similarity to other genes, and its function is unknown. C11orf23 has similarity to the SIT4 (sporulation-induced transcript 4)-associated protein (SAP) family of yeast proteins, which are involved in regulation of the cell cycle. The full-length C11orf23 cDNA is the first mammalian orthologue of the yeast SAP family to be identified. Identification of these four genes in a 400-kb region of the IDDM4 region underpins our strategy to identify the IDDM4 locus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-4-(1H-imidazol-4-ylmethyl)phenyl-methyl-urea (SCH 79687). The ...H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-alpha-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The alpha-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 microg. h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.
N-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC(50) = 58 nM) and highly selective type 4 phosphodiesterase ...(PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC(50) = 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suum-induced lung eosinophilia was blocked. Hyperventilation-induced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10- to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD.
Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid‐like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin‐induced bronchoconstriction in ...isolated guinea‐pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea‐pig nodose ganglia cells. Capsaicin increased intracellular Ca2+ concentration in these cells through activation of vanilloid receptors. Capsaicin‐induced Ca2+ responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 μM).
N/OFQ inhibitory effect on the Ca2+ response in nodose ganglia cells was antagonized by tertiapin (0.5 μM), an inhibitor of inward‐rectifier K+ channels, but not by verapamil, a voltage gated Ca2+ channel blocker, indicating that an inward‐rectifier K+ channel is involved in N/OFQ inhibitory effect.
In isolated guinea‐pig bronchus, N/OFQ (1 μM) inhibited capsaicin‐induced airway contraction. Tertiapin (0.5 μM) abolished the N/OFQ inhibition of capsaicin‐induced bronchial contraction.
Capsaicin (10 μg) increased pulmonary inflation pressure in the isolated perfused guinea‐pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 μM). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin‐induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 μM) blocked the capsaicin‐induced tachykinin release.
These results indicate that N/OFQ‐induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward‐rectifier K+ channel activation, accounts for the inhibition of capsaicin‐evoked broncoconstriction.
British Journal of Pharmacology (2002) 135, 764–770; doi:10.1038/sj.bjp.0704515
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract In vivo anesthetized guinea pigs were used to investigate the effect of tachykinin NK1 - and NK2 -receptor antagonists, as a single dose or in combination, against hyperventilation-induced ...bronchoconstriction (HIB). Guinea pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph. Hyperventilation was induced by increasing the respiratory rate from 50 to 185 breaths/min for 10 min that produced a 177±45% increase in pulmonary resistance ( RL ) and a 68±7% decrease in lung compliance ( CDyn ). Intravenous (0.03–0.3 mg/kg) and oral (0.3–10 mg/kg) pretreatments with the tachykinin NK2 -antagonist SR 48968 produced a dose-dependent inhibition of HIB whereas pretreatments with the tachykinin NK1 -antagonist CP 99994 (1 mg/kg intravenously and 30 mg/kg orally) had no effect on HIB. Intravenous and oral combinations of inactive and low doses of CP 99994 and SR 48968 produced a greater inhibition of HIB than SR 48968 alone. Also, the tachykinin NK3 -antagonist SB 223412 (1–3 mg/kg intravenously and 30 mg/kg orally) did not significantly reduce HIB although a trend was observed at the highest dose tested intravenously (3 mg/kg). We conclude that HIB in the guinea pig is mostly mediated by the tachykinin NK2 -receptors and to a lesser extent by the tachykinin NK1 -receptors. Because the hyperventilation response in guinea pigs may be a surrogate for exercise-induced obstructive airway disease in human, these results suggest that combined use of dual tachykinin NK1 - and NK2 -receptor antagonists may provide greater benefit than treatment with single activity tachykinin NK-receptor antagonist.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
48.
Cough reflex in allergic dogs HOUSE, Aileen; CELLY, Chander; SKEANS, Susan ...
European journal of pharmacology,
05/2004, Volume:
492, Issue:
2-3
Journal Article
Peer reviewed
This study investigated the effects of antigen challenge on the cough reflex in dogs that were neonatally sensitized to ragweed. Tidal volume (V(T)), respiratory rate (f), pulmonary resistance ...(R(L)), dynamic lung compliance (C(Dyn)) and the number and amplitude (increase in mean peak expiratory pressure) of coughs induced by mechanical stimulation of the intrathoracic trachea were measured in propofol-anesthetized dogs. Aerosolized ragweed challenge had no effect to induce spontaneous cough but increased f and R(L) and reduced V(T) and C(Dyn). Mechanical stimulation of the intrathoracic trachea at this time produced 19+/-5 coughs with an average increase in cough amplitude of 11+/-1 cm H(2)O which differed significantly from the number (9+/-2 coughs) and amplitude (30+/-5.5 cm H(2)O) of mechanically induced coughs after treatment with aerosolized saline. Both the number and amplitude of mechanically induced coughs returned to baseline values by 24-48 h after the ragweed challenge. Similar results were obtained after challenge with aerosolized histamine (0.3-1% histamine) that did not induce spontaneous coughs but increased f, reduced V(T) and decreased C(Dyn) and increased the number but reduced the amplitude of the mechanically induced coughs. In conclusion, both antigen and histamine bronchoprovocation changed the characteristics of the mechanically induced cough in dogs to a response of increased cough number but reduced mean expiratory cough amplitude.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A novel series of histamine H3 receptor antagonists based on the 4-(1H-imidazol-4-yl)methylpiperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural ...features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Previous studies have demonstrated that nociceptin/orphanin FQ (N/OFQ), the endogenous peptide ligand for the G-protein-coupled NOP receptor, inhibits cough in experimental models. SCH 225288 is a ...nonpeptide, orally active NOP agonist that may provide the foundation for the development of novel treatments for cough.
First we characterized the selectivity of SCH 225288 in human receptor binding assays. Afterwards, the antitussive activity of SCH 225288 was studied in three mechanistically distinct cough models. Specifically, we observed the cough-suppressant effect of SCH 225288 in a guinea pig capsaicin irritant-evoked cough model, a feline mechanically induced cough model and finally in a canine Bordetella bronchiseptica disease model.
SCH 225288 selectively binds human NOP receptor (K(i) = 0.38 +/- 0.02 nmol/l) over classical opioid receptors (COR). In a guinea pig capsaicin cough model, SCH 225288 (0.1-1 mg/kg) suppressed cough at 2, 4, and 6 h after oral administration. The antitussive effect of SCH 225288 (3.0 mg/kg, p.o.) was blocked by the NOP antagonist J113397 (12 mg/kg, i.p.) but not by the classical opioid receptor (COR) antagonist, naltrexone (3.0 mg/kg, i.p.). In the anesthetized cat, we evaluated the effects of SCH 225288 given either intravenously or via the intravertebral artery against the increases in cough number and respiratory expiratory and inspiratory muscle (rectus abdominis and parasternal) electromyographic (EMG) activities due to perturbations of the intrathoracic trachea. SCH 225288 (0.03-3.0 mg/kg, i.v.) inhibited both cough number and abdominal EMG amplitudes. Similarly, SCH 225288 (0.001-0.3 mg/kg) administered intra-arterially also diminished cough number and abdominal EMG amplitudes. No significant effect of the drug was noted on parasternal EMG activity. Finally, we studied the antitussive actions of SCH 225288 (1.0 mg/kg) in a canine B. bronchiseptica disease model. In this model, dogs were challenged intranasally with B. bronchiseptica. Comparisons were made between a vehicle group, an SCH 225288 (1.0 mg/kg, p.o., q.d.) and a butorphanol (0.6 mg/kg, p.o., b.i.d.) group on the mean change in cough scores from baseline values and days 6-9 after B. bronchiseptica challenge. SCH 225288 (1.0 mg/kg, p.o., q.d.) displayed a positive antitussive tendency (p = 0.06) to inhibit B. bronchiseptica cough whereas butorphanol (0.6 mg/kg, p.o., b.i.d.) was devoid of antitussive activity.
Taken together, the present data show that SCH 225288 is a potent and effective antitussive agent in animal models of cough. Furthermore, these findings indicate that NOP agonists represent a promising new therapeutic approach for the treatment of cough without the side effect liabilities associated with opioid antitussives.
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