The peripheral NK-1/NK-2 receptor antagonist MDL 105,172A inhibits tachykinin-mediated respiratory effects in guinea-pigs

E M Kudlacz, R W Knippenberg, S A Shatzer, J H Kehne, T C McCloskey, T P Burkholder
Journal of Autonomic Pharmacology 1997, 17 (2): 109-19
1. Stimulation of sensory nerves causes release of tachykinins, including substance P (SP) and neurokinin A (NKA), which produce a variety of respiratory effects via NK-1 and NK-2 receptors, respectively. Hence, development of a compound which could potently and equivalently antagonize both receptors was pursued. 2. MDL 105,172A ((R)-1-[3-(3,4-dicholorophenyl)-1-(3,4,5-trimethoxybenzoyl)- 3-pyrrolidinyl]-4- phenyl-piperidine-4-morpholinecarboxamide) exhibited high affinity for NK-1 (4.34 nM) and NK-2 (2.05 nM) receptors. In vitro, the compound antagonized SP (pA2 = 8.36) or NKA (pA2 = 8.61)-induced inositol phosphate accumulation in tachykinin monoreceptor cell lines. 3. In anaesthetized guinea-pigs, MDL 105,172A inhibited SP-induced plasma protein extravasation (ED50 = 1 mg kg-1, i.v.) and [beta-Ala8]NKA 4-10-induced bronchoconstriction (ED50 = 0.5 mg kg-1, i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4. Capsaicin was used to elicit respiratory effects in anaesthetized and conscious guinea-pigs; the latter were inhibited by MDL 105,172A following i.v. (ED50 = 1 mg kg-1) or oral (ED50 = 20 mg kg-1) administration. Hence, MDL 105,172A can inhibit pulmonary responses to tachykinins released endogenously in the airways. 5. At doses up to 200 mg kg-1, p.o., MDL 105,172A failed to inhibit repetitive hind paw tapping induced by i.c.v GR 73632, and NK-1 selective agonist, in gerbils, whereas CP-99,994 (0.87 mg kg-1, s.c.) completely ablated the effect. These data suggest that MDL 105,172A does not penetrate the central nervous system (CNS) and its tachykinin antagonism is restricted to the periphery. 6. MDL 105,172A is a non-peptide, potent, equivalent antagonist of NK-1 and NK-2 receptors. Its ability to inhibit both exogenously administered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.

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