Therapeutic potential of histamine H3 receptor agonists and antagonists

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Abstract

The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed.

Section snippets

Selective H3 receptor agonists and antagonists

Since the initial discovery of the H3 receptor in 1983 ([5]), major progress in the development of H3 receptor agonists and antagonists has been made. Several potent and selective agonists are currently available10, 11. Methylation of the α-carbon atom of the ethylamine side-chain of histamine leads to the potent H3 receptor agonist r-(α)-methylhistamine (Fig. 1). In combination with its less active s-isomer, this compound has been very useful for the pharmacological characterization of H3

Peripheral effects with therapeutic potential

The H3 receptor can modulate a variety of functions of important peripheral organs. In cats, dogs and rabbits, but not in rats, H3 receptor activation inhibits gastric acid secretion induced by food, pentagastrin or 2-deoxy-d-glucose[9]. This effect is secondary to the H3 receptor-induced inhibition of the release of acetylcholine, histamine or somatostatin from vagal nerve endings, enterochromaffin-like (ECL) cells and D cells (somatostatin-releasing cells), respectively[9]. Because of the

Sleep and wakefulness

The presence of histamine-containing cell bodies in the tuberomamillary nucleus of the posterior hypothalamus (an area involved in the maintenance of wakefulness) and their projections to the cerebral cortex suggest a role of histamine in the modulation of the arousal state and sleep–wake cycle. Lesions of the posterior hypothalamus are known to produce sleep in rats, cats and monkeys[31], and neurochemical and electro-physiological studies indicate that the activity of histamine-containing

Cognition and memory processes

Dysfunctions of acetylcholine-mediated neurotransmission are considered to underlie the cognitive decline associated with ageing and Alzheimer's disease. However, changes typical of ageing and Alzheimer's disease occur within the context of alterations of other neurotransmitter systems, including histamine39, 40. Histamine levels in the hypothalamus, hippocampus and temporal cortex have been found to be significantly lower in brains from patients with Alzheimer's disease compared with controls

Attention-deficit hyperactive disorder

Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder with underlying emotional, attentional and learning disabilities. The disorder has an onset in early childhood (there are approximately three million sufferers in the USA) and over 50% of those children diagnosed with ADHD will continue to experience attentional problems as adults[55]. Underlying abnormalities in monoamine neurotransmitters appear to significantly contribute to the learning and motor disturbances in

Epilepsy

Almost 50 years ago, the first clinical indications suggesting the involvement of central histamine-mediated neurotransmission in epilepsy were reported62, 63. In epileptic patients and healthy young children (especially of pre-school age), several brain-penetrating H1 receptor antagonists occasionally induce convulsions62, 63, 64. Moreover, direct H1 receptor activation or modulation of CNS histamine levels by l-histidine loading, inhibition of histamine synthesis or metabolism in rodents has

Concluding remarks

Important progress has recently been made in the understanding of the role of the H3 receptor. Clear indications for the potential therapeutic use of H3 receptor agonists and antagonists are now available, and clinical trials are in progress or being planned. For H3 receptor agonists especially, the feedback mechanism on sensory C fibres and resultant anti-inflammatory effects suggest a poten-tial peripheral application in the treatment of asthma, migraine, cardiac disorders and inflammatory

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