SK&F 93944 (
temelastine), a novel
histamine H1-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems.
SK&F 93944 was a competitive antagonist of
histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of
histamine on guinea-pig atrium. In anaesthetized guinea-pigs
SK&F 93944 displaced
histamine bronchoconstriction dose-response curves at doses which had negligible effects on
histamine tachycardia. In anaesthetized cats
SK&F 93944 antagonized depressor responses to the
histamine H1-receptor agonists,
2-(2-aminoethyl)pyridine and
betahistine, at doses which had no effects on responses to the
histamine H2-receptor agonist,
dimaprit. Oral pretreatment with
SK&F 93944 in conscious rats and guinea-pigs afforded protection versus the response to intradermal
histamine injection. Comparative studies in each of the test systems showed that
SK&F 93944 was of comparable or significantly greater potency than the standard compound,
mepyramine.
SK&F 93944 was found to be a weak, non-competitive antagonist of
carbachol on the guinea-pig ileum but was devoid of measurable
anticholinergic activity in vivo. Studies on the penetration of [14C]-
SK&F 93944, labelled either in the
isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady-state blood concentrations. In contrast, brain concentrations of [3H]-
mepyramine exceeded blood concentrations by
a factor of approximately 3.
SK&F 93944 may have an advantage over classical
histamine H1-receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.