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Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H 1 ‐receptor antagonist with negligible ability to penetrate the central nervous system
Author(s) -
Brown E. Ann,
Griffiths R.,
Harvey Carol A.,
Owen D.A.A.
Publication year - 1986
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1986.tb10199.x
Subject(s) - histamine , dimaprit , mepyramine , carbachol , histamine h2 receptor , chemistry , pharmacology , histamine h1 receptor , agonist , medicine , antagonist , metiamide , endocrinology , histamine receptor , guinea pig , histamine h1 antagonists , receptor , biology , biochemistry
1 SK&F 93944 (temelastine), a novel histamine H 1 ‐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 pA 2 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 H 1 ‐receptor agonists, 2‐(2‐aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H 2 ‐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 [ 14 C]‐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 [ 3 H]‐mepyramine exceeded blood concentrations by a factor of approximately 3. 9 SK&F 93944 may have an advantage over classical histamine H 1 ‐receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.