MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist
| Autor: | Claudio Catalani, Claudio Valenti, Cecilia Cialdai, Carlo Alberto Maggi, Manuela Tramontana, Stefania Meini, Sandro Giuliani, Rose-Marie Catalioto, Maria Altamura, Alessandro Lecci, Riccardo Patacchini |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Agonist medicine.medical_specialty Colon Swine medicine.drug_class Bronchoconstriction Neurokinin A Guinea Pigs Pig bladder Substance P CHO Cells Thiophenes In Vitro Techniques Pharmacology Binding Competitive Mice Radioligand Assay chemistry.chemical_compound Cricetulus In vivo Cricetinae Internal medicine medicine Animals Humans Potency Rats Wistar Receptor Aged Dose-Response Relationship Drug Cell Membrane Antagonist Dipeptides Receptors Neurokinin-2 Middle Aged Peptide Fragments Rats Endocrinology chemistry Vasoconstriction Female Rabbits Muscle Contraction |
| Zdroj: | European Journal of Pharmacology. 549:140-148 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2006.08.021 |
| Popis: | The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect