Maria Teresa Pulido-Rios

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Through application of our multivalent approach to drug discovery we previously reported the first discovery of dual pharmacology MABA bronchodilators, exemplified by 1. Herein we describe the subsequent lead optimization of both muscarinic antagonist and β2 agonist activities, through modification of the linker motif, to achieve 24 h duration of action in(More)
5-HT4 receptors in isolated distal colon myenteric plexus of guinea-pig, mediating contraction of longitudinal smooth muscle, have been further characterized by selective agonists and antagonists. The indole agonists, 5-HT and 5-methoxytryptamine (5-MeOT), were full agonists (relative to 5-HT) with potency values (pEC50) of 8.0 ± 0.1 (n = 50) and 7.8 ± 0.1(More)
1. 5-Hydroxytryptamine (5-HT) receptors mediating contraction and relaxation are present in Cynomolgus monkey isolated jugular vein denuded of endothelium. 2. In the absence of spasmogen, alpha-methyl-5-HT and sumatriptan contracted the tissues with potency values (pEC50) of 6.8 (n = 2) and 6.4 +/- 0.1 (mean +/- s.e. mean, n = 3), respectively. In contrast,(More)
Combinations of a muscarinic receptor antagonist (MA) and a β(2)-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495(More)
INTRODUCTION The discovery of novel bronchodilators that treat human respiratory disorders has been guided by an array of animal models of bronchoconstriction which differ in technical complexity and experimental endpoints. Here, we apply methodology in which ventilation pressure provides a surrogate measure of airway tone (Einthoven, 1892) to assess the(More)
1. Relaxations of isolated oesophageal muscularis mucosae of rat are mediated by 5-hydroxytryptamine (5-HT), acting at 5-HT4 receptors, and isoprenaline, principally acting via beta 3-adrenoceptors. The aim of this study was to investigate the hypothesis that muscarinic M2 receptors, also present in this tissue, functionally oppose 5-HT and(More)
G-protein-coupled muscarinic receptors (mAChRs), of which there are five subtypes (M(1)-M(5)), are attractive drug targets for a number of disorders. Described in this unit are radioligand-binding assays for defining the selectivity and affinity of chemical agents at the five mAChR subtypes. Detailed methodologies and troubleshooting strategies are provided(More)
Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe(More)
The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,19-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing(More)
Muscarinic receptor (mAChRs) subtypes are viable targets for the design of novel agents for use in a number of central and peripheral disorders. In vitro isolated tissue functional assays for muscarinic receptor subtypes have played an invaluable role in basic research and drug discovery. The availability of biological assays for generation of quantitative(More)