The histamine H 3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H 3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H 3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H 3 receptors by selective H 3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H 3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H 3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H 3 receptor antagonist has been reported to date. The discovery of effective H 3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H 3 receptor.

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In this article, we pharmacologically characterized two naturally occurring human histamine H 3 receptor (hH 3 R) isoforms, hH 3 R(445) and hH 3 R(365). These abundantly expressed splice variants differ by a deletion of 80 amino acids in the intracellular loop 3. In this report, we show that the hH 3 R(365) is differentially expressed compared with the hH 3 R(445) and has a higher affinity and potency for H 3 R agonists and conversely a lower potency and affinity for H 3 R inverse agonists. Furthermore, we show a higher constitutive signaling of the hH 3 R(365) compared with the hH 3 R(445) in both guanosine-5Ј-O-(3-[35 S]thio)triphosphate binding and cAMP assays, likely explaining the observed differences in hH 3 R pharmacology of the two isoforms. Because H 3 R ligands are beneficial in animal models of obesity, epilepsy, and cognitive diseases such as Alzheimer's disease and attention deficit hyperactivity disorder and currently entered clinical trails, these differences in H 3 R pharmacology of these two isoforms are of great importance for a detailed understanding of the action of H 3 R ligands.The histamine H 3 receptor (H 3 R) was originally discovered in the brain on histaminergic neurons as a presynaptic autoreceptor regulating the release of histamine (Arrang et al., 1983). Subsequently, the H 3 R was found to regulate the release of other neurotransmitters, such as acetylcholine, dopamine, glutamate, noradrenalin, and serotonin (Schlicker et al., 1988(Schlicker et al., , 1989(Schlicker et al., , 1993Clapham and Kilpatrick, 1992;Brown and Reymann, 1996). The histamine-containing cell bodies, located in the tuberomammillary nucleus of the posterior hypothalamus, project to most cerebral areas in rodent and human brain (Panula et al., 1984;Watanabe et al., 1984). Brain histamine is involved in the regulation of numerous functions of the central nervous system (CNS), including arousal, cognition, locomotor activity, autonomic and vestibular functions, feeding and drinking, sexual behavior, and analgesia (Hough, 1988;Schwartz et al., 1991;Wada et al., 1991). Moreover, H 3 R-specific ligands show beneficial effects in animal models of obesity, epilepsy, and cognitive diseases such as Alzheimer's disease and attention deficit hyperactivity disorder (Hancock, 2003;Passani et al., 2004;Leurs et al., 2005). Consequently, H 3 R antagonists are con-1

Mounting evidence suggests excessive glucocorticoid activity may contribute to Alzheimer's disease (AD) and age-associated memory impairment. 11␤-hydroxysteroid dehydrogenase type-1 (HSD1) regulates conversion of glucocorticoids from inactive to active forms. HSD1 knock-out mice have improved cognition, and the nonselective inhibitor carbenoxolone improved verbal memory in elderly men. Together, these data suggest that HSD1 inhibition may be a potential therapy for cognitive deficits, such as those associated with AD. To investigate this, we characterized two novel and selective HSD1 inhibitors, A-918446 and A-801195. Learning, memory consolidation, and recall were evaluated in mouse 24 h inhibitory avoidance. Inhibition of brain cortisol production and phosphorylation of cAMP response element-binding protein (CREB), a transcription factor involved in cognition, were also examined. Rats were tested in a short-term memory model, social recognition, and in a separate group cortical and hippocampal acetylcholine release was measured via in vivo microdialysis. Acute treatment with A-801195 (10 -30 mg/kg) or A-918446 (3-30 mg/kg) inhibited cortisol production in the ex vivo assay by ϳ35-90%. Acute treatment with A-918446 improved memory consolidation and recall in inhibitory avoidance and increased CREB phosphorylation in the cingulate cortex. Acute treatment with A-801195 significantly improved short-term memory in rat social recognition that was not likely due to alterations of the cholinergic system, as acetylcholine release was not increased in a separate set of rats. These studies suggest that selective HSD1 inhibitors work through a novel, noncholinergic mechanism to facilitate cognitive processing.

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.