Antibronchospastic activity of MEN10,627, a novel tachykinin NK2 receptor antagonist, in guinea-pig airways.
The antibronchospastic activity against acetylcholine, antigen, histamine plus platelet-activating factor (PAF) or the selective tachykinin neurokinin (NK)1 and NK2 receptor agonists of the novel tachykinin NK2 receptor antagonist, MEN10,627 (cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta)), was studied in anesthetized guinea-pigs. MEN10,627 (30-100 nmol/kg i.v.) reduced in a dose-dependent manner the bronchospasm induced by the tachykinin NK2 receptor agonist [beta Ala8]neurokinin A-(4-10) and the effect of the highest dose lasted up to 5 h from its administration. Conversely, airway constriction induced by the NK1 receptor agonist [Sar9]substance P sulfone or acetylcholine was unaffected by MEN10,627 up to a dose of 3 mumol/kg i.v. In animals sensitized with ovalbumin and pretreated with the endopeptidase inhibitor phosphoramidon, the aerosolized antigen produced a bronchospasm which was inhibited by MEN10,627 (30-100 nmol/kg i.v.) but not by the tachykinin NK1 receptor antagonist, (+/-)-CP96,345 ([2R,3R-cis- and [2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1- azabicyclo[2.2.2]octan-3-amine]) (3 mumol/kg i.v.). Both MEN10,627 (30-100 nmol/kg i.v.) and (+/-)-CP96,345 (30-300 nmol/kg i.v.) reduced the PAF-induced hyperresponsiveness to histamine, without affecting the hypotension induced by PAF or the bronchospasm induced by histamine in guinea-pigs not exposed to PAF, showing the involvement of both tachykinin NK1 and NK2 receptors in this model. In summary, MEN10,627 behaves as a potent, selective and long-lasting tachykinin NK2 receptor antagonist in vivo. Further, tachykinin NK2 receptors could be activated during allergic responses and in the development of airway hyperresponsiveness.
Perretti
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Pharmacology Department, Istituto Farmacobiologico Malesci S.p.A., Florence, Italy.
Ballati
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Manzini
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Maggi
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Evangelista
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D000109:Acetylcholine / Q000494:pharmacology; D000399:Air Pressure; D000595:Amino Acid Sequence; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D012137:Respiratory System / Q000187:drug effects*
D001713:Biphenyl Compounds; D001993:Bronchodilator Agents; D006993:Hypnotics and Sedatives; D010456:Peptides, Cyclic; D010972:Platelet Activating Factor; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C090951:MEN 10627; D006632:Histamine; D000109:Acetylcholine; C066892:CP 96345