BIOAVAILABILITY, ANTINOCICEPTIVE AND ANTIINFLAMMATORY PROPERTIES OF BP-2-94, A HISTAMINE H-3 RECEPTOR AGONIST PRODRUG

(R)alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective hista mine H-3 receptor agonist in vitro and in vivo in rodents, was found t o display comparatively low plasma level in healthy human volunteers, attributable to an extensive methylation of the drug's imidazole ring by histamine-N-methyltransferase. To limit this inactivation process, BP 2-94, i.e., [1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl] phen ol, was selected as a prodrug. A sensitive radioimmunoassay was develo ped to study the generation of (R)alpha-MeHA slowly released from BP 2 -94 in vitro and in vivo by chemical hydrolysis. In mice after oral ad ministration of BP 2-94 high levels of both prodrug and (R)alpha-MeHA were detected in plasma and various tissues except in the brain. In hu mans receiving 0.1 mmol BP 2-94 orally, plasma levels of (R)alpha-MeHA -like immunoreactivity decayed with a t(1/2) more than 24 hr, the area under the curve being two orders of magnitude higher than after oral administration of (R)alpha-MeHA. BP 2-94 displayed antiinflammatory an d antinociceptive properties in rodents, related to the H-3 receptor s timulation. It dose-dependently inhibited capsaicin-induced plasma pro tein extravasation in many rat tissues with ED(50)s of 0.6 to 14 mu mo l/kg p.o., and maximal reductions by 35 to 87%. BP 2-94 also reduced z ymosan-induced paw swelling in mice with an ED50 of 1 mu mol/kg p.o, a nd showed marked activity in the phenylbenzoquinone-induced writhing ( ED50 = 0.03 mu mol/kg, p.o.) or formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological pr ofile BP 2-94 appears to be a promising novel therapeutic agent in dis orders such as asthma, migraine or a variety of inflammatory diseases and pain associated with these disorders.