Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist with negligible ability to penetrate the central nervous system.

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.