title: In vitro and in vivo characterization of MDL 105,212A, a nonpeptide NK-1/NK-2 tachykinin receptor antagonist.
abstract: We have identified and characterized a novel, potent, nonselective tachykinin receptor antagonist, MDL 105,212A [(R)-1-[2-[3-(3,4- dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl] -ethyl]- 4-phenylpiperidine-4-carboxamide, hydrochloride]. The compound binds with low nanomolar affinity and species specificity to human NK-1 and NK-2 receptors as well as to guinea pig NK-3 receptors. In vitro functional assays are consistent with potent competitive antagonism of substance P-(SP) or neurokinin A-(NKA) induced [3H]-inositol phosphate accumulation in NK-1 or NK-2 monoreceptor cell lines with pA2 values of 8.19 and 8.67, respectively. Its ability to inhibit SP, NKA and capsaicin-mediated respiratory effects was examined in guinea pigs in vivo. MDL 105,212A attenuated SP-induced airway plasma protein extravasation (ED50 = 0.20 mg/kg, i.v.), NKA-induced respiratory collapse (ED50 = 5 mg/kg, i.v) and inhibited capsaicin-induced increases in pulmonary insufflation pressure (ED50 = 0.5 mg/kg, i.v.). Conscious guinea pigs responded to capsaicin aerosol exposure with dyspnea, coughs and gasps (significant respiratory events) and plasma protein extravasation. MDL 105,212A inhibited these responses in a dose-dependent manner after i.v. (ED50 = 5 mg/kg) or oral (ED50 = 50 mg/kg) administration. These data suggest that MDL 105,212A is a potent NK-1 and NK-2 receptor antagonist based on in vitro activity and its ability to inhibit SP and NKA mediated respiratory effects in vivo after exogenous administration or endogenous release and hence may be a useful therapeutic agent in neuroinflammatory disorders such as asthma in which a role for both tachykinins in the pathogenesis of the disease has been postulated.
authors.affiliation: Hoechst Marion Roussel, Cincinnati, Ohio, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Kudlacz
authors.forename: S A
authors.initials: SA
authors.lastname: Shatzer
authors.forename: R W
authors.initials: RW
authors.lastname: Knippenberg
authors.forename: D E
authors.initials: DE
authors.lastname: Logan
authors.forename: M
authors.initials: M
authors.lastname: Poirot
authors.forename: P L
authors.initials: PL
authors.lastname: van Giersbergen
authors.forename: T P
authors.initials: TP
authors.lastname: Burkholder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012119:Respiration / Q000187:drug effects; D013045:Species Specificity; D013373:Substance P / Q000037:antagonists & inhibitors
chemical_list: D007295:Inositol Phosphates; C099415:MDL 105212A; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D018041:Receptors, Neurokinin-2; D016210:Methacholine Chloride; D013373:Substance P; D015288:Neurokinin A