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This article reviews the development of our knowledge of the actions of histamine which have taken place during the course of the 20th century. Histamine has been shown to have a key physiological role in the control of gastric acid secretion and a pathophysiological role in a range of allergic disorders. The synthesis of, and pharmacological studies on, selective agonists and antagonists has established the existence of four types of histamine receptor and histamine receptor antagonists have found very important therapeutic applications. Thus, in the 1940s, H 1 -receptor antagonists ('the antihistamines') yielded and still provide valuable treatment for allergic conditions such as hay fever and rhinitis. In the late 1970s and 1980s, H 2 -receptor antagonists (in the discovery of which the two authors were personally involved) revolutionised the treatment of peptic ulcer and other gastric acid-related diseases. The H 3 -receptor antagonists, although available since 1987, have been slower to find a therapeutic role. However, the discovery of nonimidazole derivatives such as brain-penetrating H 3 antagonists has provided drugs that are in early-phase clinical trials, possibly for application in obesity, and a variety of central nervous system disorders, such as memory, learning deficits and epilepsy. Finally, the most recently (1999) discovered H 4 receptor promises the potential to provide drugs acting on the immunological system with possible applications in asthma and inflammation.

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Histamine H 3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H 3 receptor. On the stimulation of guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K i value of 0.16 nM and as an inverse agonist with an EC 50 value of 1.5 nM and an intrinsic activity ϳ50% higher than that of ciproxifan. Its in vitro potency was ϳ6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED 50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.The cerebral histaminergic neurons seem to play a critical role in the maintenance of wakefulness and higher cerebral functions, e.g., attention or learning (for review, see Schwartz et al., 1991;Haas and Panula, 2003). Hence, druginduced activation of histaminergic neurotransmission in the central nervous system represents a promising therapeutic target in a large variety of neuropsychiatric disorders in which these functions are compromised and for which available therapeutic opportunities are limited in this respect .Stimulation of postsynaptic H 1 and/or H 2 receptors by agonists is, however, not acceptable due to unavoidable and detrimental actions of these drugs at peripheral, i.e., mainly cardiovascular and gastric targets. In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al., Article, publication date, and citation information can be found at