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

1 SK&F 93944 (temelastine), a novel histamine H1‐receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. 2 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. 3 In anaesthetized guinea‐pigs SK&F 93944 displaced histamine bronchoconstriction dose‐response curves at doses which had negligible effects on histamine tachycardia. 4 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. 5 Oral pretreatment with SK&F 93944 in conscious rats and guinea‐pigs afforded protection versus the response to intradermal histamine injection. 6 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. 7 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. 8 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. 9 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.