Therapeutic potential of Histamine H3 receptor agonists and antagonists

Numerous studies dissecting the basic mechanisms that control sleep regulation have led to considerable improvement in our knowledge of sleep disorders It is now well accepted that transitions between sleep and wakefulness are regulated by complex neurobiologic mechanisms, which, ultimately, can be delineated as oscillations between two opponent processes, one promoting sleep and the other promoting wakefulness The role of several neurotransmitter or neuromodulator systems, including noradrenergic, serotonergic, cholinergic, adenosinergic, and histaminergic systems and, more recently, the hypocretin/orexin and dopamine systems, has been clearly established Amphetamine-like stimulants are known to increase wakefulness by blocking dopamine reuptake, by stimulating dopamine release, or by both mechanisms Modafinil may increase wakefulness through activation of noradrenergic and dopaminergic systems, possibly through interaction with the hypocretin/orexin system Caffeine inhibits adenosinergic receptors, which in turn can produce activation via interaction with GABAergic and dopaminergic neurotransmission Nicotine enhances acetylcholine neurotransmission in the basal forebrain and dopamine release Understanding the exact role of the hypocretin/orexin and dopamine systems in the physiology and pharmacology of sleep-wake regulation may reveal new insights into current and future wakefulness-promoting drugs

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What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications.

Ciproxifan, i.e., cyclopropyl-(4-(3-1H-imidazol-4-yl)propyloxy) phenyl) ketone, belongs to a novel chemical series of histamine H3-receptor antagonists. In vitro, it behaved as a competitive antagonist at the H3 autoreceptor controlling [3H]histamine release from synaptosomes and displayed similar Ki values (0.5-1.9 nM) at the H3 receptor controlling the electrically-induced contraction of guinea pig ileum or at the brain H3 receptor labeled with [125I]iodoproxyfan. Ciproxifan displayed at least 3-orders of magnitude lower potency at various aminergic receptors studied in functional or binding tests. In vivo, measurement of drug plasma levels, using a novel radioreceptor assay in mice receiving ciproxifan p.o. or i.v., led to an oral bioavailability ratio of 62%. Oral administration of ciproxifan to mice enhanced by approximately 100% histamine turnover rate and steady state level of tele-methylhistamine with an ED50 of 0.14 mg/kg. Ciproxifan reversed the H3-receptor agonist induced enhancement of water consumption in rats with and ID50 of 0.09 +/- 0.04 mg/kg, i.p. In cats, ciproxifan (0.15-2 mg/kg, p.o.) induced marked signs of neocortical electroencephalogram activation manifested by enhanced fast-rhythms density and an almost total waking state. In rats, ciproxifan enhanced attention as evaluated in the five-choice task performed using a short stimulus duration. Ciproxifan appears to be an orally bioavailable, extremely potent and selective H3-receptor antagonist whose vigilance- and attention-promoting effects are promising for therapeutic applications in aging disorders.

Neurochemical and Behavioral Effects of Ciproxifan, A Potent Histamine H3-Receptor Antagonist

Many neurochemical systems interact to generate wakefulness and sleep. Wakefulness is promoted by neurons in the pons, midbrain, and posterior hypothalamus that produce acetylcholine, norepinephrine, dopamine, serotonin, histamine, and orexin/hypocretin. Most of these ascending arousal systems diffusely activate the cortex and other forebrain targets. NREM sleep is mainly driven by neurons in the preoptic area that inhibit the ascending arousal systems, while REM sleep is regulated primarily by neurons in the pons, with additional influence arising in the hypothalamus. Mutual inhibition between these wake- and sleep-regulating regions likely helps generate full wakefulness and sleep with rapid transitions between states. This up-to-date review of these systems should allow clinicians and researchers to better understand the effects of drugs, lesions, and neurologic disease on sleep and wakefulness.

http://www.neuroscience.ubc.ca/CourseMat/Scammell_Neurobiology_of_sleep.pdf

Jaime M Monti

Papers

Sleep and Waking during Acute Histamine H3 Agonist BP 2.94 or H3 Antagonist Carboperamide (MR 16155) Administration in Rats