Two Novel and Selective Nonimidazole H₃ Receptor Antagonists A-304121 and A-317920: II. In Vivo Behavioral and Neurophysiological Characterization

Abstract

Pharmacological blockade of central histamine H 3 receptors (H 3 Rs) enhances cognition in rodents and offers promise for the clinical treatment of neurological disorders. However, many previously characterized H 3 R antagonists are either not selective for H 3 Rs or have potentially significant tolerability issues. Here, we present in vivo behavioral and neurophysiological data for two novel and selective H 3 R antagonists with improved safety indices. (1 mg/kg). Social memory was also significantly enhanced in the adult rat with A-304121 (3, 10 mg/kg) and A-317920 (1, 3 mg/kg) at doses that produced no significant change in electroencephalogram slow-wave amplitude activity. Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, by comparing doses producing adverse effects in general observation studies with potency in inhibitory avoidance, which were superior to TIs of 8, 10, and 18 observed for the reference antagonists thioperamide, ciproxifan, and GT-2331, respectively. A-304121 and A-317920 represent a series of novel, H 3 R-selective piperazine amides that enhance cognition in vivo, which could offer advantages over existing H 3 R antagonists or cognition-enhancing agents.

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…injections of Pitolisant also enhance consolidation in the contextual fear conditioning paradigm. These results are in agreement with previous experiments demonstrating that the systemic injection of H 3 R inverse agonists facilitates memory consolidation in the passive avoidance task [17], the social memory test [18,19] and the two-trail place recognition task [20]. Together, these data indicate that H 3 R inverse agonists have beneficial effects on different aspects of memory but the neuronal mechanisms underlying these effects are still unclear.…”

“…In addition, other neurotransmitter systems like histamine can facilitate the consolidation of memories [16]. The systemic injection of H 3 R inverse agonists improve consolidation in the inhibitory avoidance test [17], the social memory test [18,19], the two-trail place recognition task [20] and the fear conditioning task [14].…”

Acute Inhibition of 11β-Hydroxysteroid Dehydrogenase Type-1 Improves Memory in Rodent Models of Cognition

“…Social recognition methods are similar to those described previously (Fox et al, 2003). In this test of short-term memory, an adult rat interacts with an unfamiliar juvenile rat for 5 min.…”

The H3 receptor protean agonist proxyfan enhances the expression of fear memory in the rat

“…There is convincing evidence that systemic administration of such compounds in experimental animals have procognitive effects in learning paradigms such as the five-choice, serial reaction time task (Ligneau et al, 1998), the object recognition test (Giovannini et al, 1999), the two-choice place recognition test (Orsetti et al, 2001), the five-trial inhibitory avoidance test (Fox et al, 2002a(Fox et al, , 2003, the elevatedplus maze task (Onodera et al, 1998) and in social memory (Fox et al, 2003). However, when administered locally, into restricted brain regions H 3 ligands may have other effects on the expression of some forms of memory.…”