THE PERIPHERAL NK-1 NK-2-RECEPTOR ANTAGONIST MDL-105,172A INHIBITS TACHYKININ-MEDIATED RESPIRATORY EFFECTS IN GUINEA-PIGS/

1 Stimulation of sensory nerves causes release of tachykinins, includi ng 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 antag onize both receptors was pursued. 2 MDL 105,172A yl)-1-(3,4,5-trimetho xybenzoyl)-3-pyrrolidinyl]-4- phenyl-piperidine-4-morpholinecarboxamid e) exhibited high affinity for NK-1 (4.34 nM) and NK-2 (2.05 nM) recep tors. In vitro, the compound antagonized SP (pA(2) = 8.36) or NKA (pA( 2) = 8.61)-induced inositol phosphate accumulation in tachykinin monor eceptor cell lines. 3 In anaesthetized guinea-pigs, MDL 105,172A inhib ited SP-induced plasma protein extravasation (ED50 = 1 mg kg(-1), i.v. ) and [beta-Ala(8)]NKA 4-10-induced bronchoconstriction (ED50 = 0.5 mg kg(-1), i.v.) indicating NK-1 and NK-2 antagonism, respectively. 4 Ca psaicin was used to elicit respiratory effects in anaesthetized and co nscious guinea-pigs; the latter were inhibited by MDL 105,172A followi ng i.v. (ED50 = 1 mg kg(-1)) or oral (ED50 = 20 mg kg(-1)) adminstrati on. 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 indu ced by i.c.v. GR 73632, an 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 perip hery. 6 MDL 105,172A is a non-peptide, potent, equivalent antagonist o f NK-1 and NK-2 receptors. Its ability to inhibit both exogenously adm inistered as well as endogenously released tachykinins support its use in examining the role of sensory neuropeptides in diseases associated with neurogenic inflammation including asthma.