(R)
alpha-Methylhistamine [(R)alpha-MeHA], a potent and selective
histamine H3 receptor agonist in vitro and in vivo in rodents, was found to 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, ie., (R)-(-)-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino]phenylmethyl]
phenol, was selected as a
prodrug. A sensitive radioimmunoassay was developed 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 administration 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 humans 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 and antinociceptive properties in rodents, related to the
H3 receptor stimulation. It dose-dependently inhibited
capsaicin-induced
plasma protein extravasation in many rat tissues with ED50s of 0.6 to 14 micromol/kg p.o., and maximal reductions by 35 to 87%.
BP 2-94 also reduced
zymosan-induced paw swelling in mice with an ED50 of 1 micromol/kg p.o. and showed marked activity in the
phenylbenzoquinone-induced writhing (ED50 = 0.03 micromol/kg, p.o.) or
formalin tests in mice, but not in the hot plate jump test. From its pharmacokinetics and pharmacological profile
BP 2-94 appears to be a promising novel therapeutic agent in disorders such as
asthma,
migraine or a variety of inflammatory diseases and
pain associated with these disorders.