Identification of novel H 3 receptor (H 3 R) antagonists with cognition enhancing properties in rats

Abstract

IntroductionPharmacological blockade of central H 3 receptors (H 3 R) enhances learning and attention and attenuates cognitive deficits induced by scopolamine in several animal models [1,2]. Consequently, H 3 R ligands are potential therapeutic agents for the treatment of CNS disorders in which cognitive deficits are evident [3]. However, previously characterized compounds that share the imidazole moiety with the endogenous agonist, histamine, are not selective for H 3 R or have potentially significant tolerability issues [1,4]. We now present behavioral data for two novel and selective, non-imidazole H 3 R antagonists. Materials and methodsA-304121 (2-Amino-1-{4-[3-(4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl}-propan-1-one) and A-317920 (Furan-2-carboxylic acid (2-{4-[3-(4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl}-1-methyl-2-oxo-ethyl)-amide), were synthesized at Abbott [5] and evaluated in a repeated acquisition, avoidance model using methods similar to those previously described [1]. Briefly, male spontaneously hypertensive rat (SHR) pups (postnatal day 20 -24) were trained to avoid a mild footshock (0.1 mA, 1 s duration), delivered when the pup transferred from a brightly lit to a darkened compartment. After the first trial, the pup was removed and returned to its home cage. One min later, the same pup was replaced in the brightly lit compartment and the training process repeated for a total of five trials. Compounds were injected subcutaneously 30 min prior to training. A-304121 was also evaluated in a social memory test. Adult male Sprague-Dawley rats (350 -450 g) were separated into fresh investigation cages and allowed to habituate for 30 min. An unfamiliar juvenile was introduced and the investigation (grooming, sniffing, close following) duration recorded over a 5 min period. Both the adult and juvenile were then removed to their respective holding cages. After 90 min, the adult was replaced into the same investigation cage and the same juvenile reintroduced 30 min later: investigation duration was again recorded. A-304121 was administered intraperitoneally to the adult rat immediately after the first exposure period. For acute safety measures, adult male CD-1 mice (n = 3 per group) were injected intraperitoneally with increasing doses of thioperamide (Tocris, UK), ciproxifan, GT-2331, A-304121, or A-317920 (all synthesized at Abbott) until serious adverse effects were encountered. Results and discussionPerformance of SHR pups administered A-304121 (10 mg/ kg) or A-317920 (3,10 mg/kg) was significantly improved in the avoidance test when compared with saline controls (Fig. 1a, b). Since this test was conducted over a discrete time period (15 min) and utilized SHR pups, it is likely that these data reflect improved learning and/or attention [1]. Thioperamide, ciproxifan and GT-2331 were similarly efficacious in previous studies at 10, 3 and 1 mg/kg, respectively [1]. However, when assessed acutely in the safety test, thioperamide, ciproxifan and GT-2331 induced serious adverse eff...

Detection of low level histamine H3 receptor occupancy by autoradiography

“…H 3 R antagonists have been proposed as a novel approach to the treatment of cognitive, attentional, and sleep disorders (Esbenshade et al, 2008;Hudkins and Raddatz, 2007;Stocking and Letavic, 2008). Interestingly, H 3 R antagonists produce in vivo effects in preclinical animal models across a wide dose range (Barbier et al, 2004;Fox et al, 2003;Medhurst et al, 2007a,b), suggesting that efficacy in different models may be produced by varying levels of receptor occupancy. Therefore, an understanding of the relationship between H 3 R antagonist efficacy in the preclinical models and H 3 R occupancy would lead to a better understanding of the preclinical models and potentially provide guidelines for dosing.…”

Correlation between ex Vivo Receptor Occupancy and Wake-Promoting Activity of Selective H3 Receptor Antagonists

“…These models include social recognition (Fox et al, 2003a(Fox et al, ,b, 2005, novel object recognition (Fox et al, 2005;Ligneau et al, 2007;Medhurst et al, 2007a), spatial learning and memory in an This study was supported by Cephalon, Inc. Article, publication date, and citation information can be found at…”

“…These models include social recognition (Fox et al, 2003a(Fox et al, ,b, 2005, novel object recognition (Fox et al, 2005;Ligneau et al, 2007;Medhurst et al, 2007a), spatial learning and memory in an adult rat water maze test (Fox et al, 2005), scopolamine-induced deficits in memory consolidation in a passive avoidance test (Medhurst et al, 2007b), and cortical electroencephalographic (EEG) recording (Barbier et al, 2004;Ligneau et al, 2007).…”

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

“…The ability of H 3 receptor antagonists to facilitate acetylcholine, dopamine, and glutamate release has generated considerable interest in their therapeutic potential for a variety of neurologic and psychiatric disorders, particularly diseases with attendant neurocognitive deficits. Indeed, H 3 receptor antagonists enhance behavioral performance in a variety of rodent learning paradigms (Fox et al, 2003Foley et al, 2009) and reversed contextual fear conditioning and spatial navigation deficits in fetal ethanol-exposed Long-Evans rats (Savage et al, 2010).…”