Sedation and histamine H₁‐receptor antagonism: studies in man with the enantiomers of chlorpheniramine and dimethindene

Abstract

1 The effects of 10mg (+)-and (-)-chlorpheniramine and 5mg (+)-and (-)-dimethindene on daytime sleep latencies, digit symbol substitution and subjective assessments of mood and well-being were studied in 6 healthy young adult humans. Each subject also took 5mg triprolidine hydrochloride as an active control and two placebos. 2 Daytime sleep latencies were reduced with triprolidine, (+)-chlorpheniramine and (-)-dimethindene, and subjects also reported that they felt more sleepy after (+)-chlorpheniramine and (-)-dimethindene. Performance on digit symbol substitution was impaired with (+ )-chlorpheniramine. 3 Changes in measures with (-)-chlorpheniramine and (+)-dimethindene were not different from changes with placebo. 4 In the present study, changes in measures of drowsiness and performance were limited to the enantiomers with high affinity for the histamine Hl-receptor. These findings strongly suggest that sedation can arise from H1-receptor antagonism alone, and provide further support for the belief that the histaminergic system is concerned with the regulation of alertness in man.

Histamine H1 receptor occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography

“…Many antihistamines cause drowsiness and impaired performance (Nicholson, 1983;1987), which are thought to be due mainly to their blockade of central histamine HI receptors (Nicholson et al, 1991). However, there has been a resurgence of interest in histamine HI receptor antagonists since the recent discovery and development of antihistamines with low, if any, side effects of sedation (Ganellin, 1992).…”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Diphenhydramine (6), doxylamine (7), mepyramine (pyrilamine; 8), doxepine, dimetinden (9), and bamipine are a few examples based on this general construction pattern. These compounds have in common that they easily cross the blood-brain barrier causing sedation (Nicholson et al, 1991) and/or anticholinergic effects (Hill, 1990). At higher dosages, numerous examples of these compounds also display anesthetic effects that may have some therapeutic advantages on topical applications for urticaria or itch (Orhan et al, 2007;Murota and Katayama, 2011).…”

New substituted indene derivatives from bicyclic Baylis-Hillman acetate

“…These compounds are important model structures found in various natural products [1][2][3] and bioactive compounds [4][5][6][7] ( Figure 1). …”