Correlating Efficacy in Rodent Cognition Models with in Vivo 5-Hydroxytryptamine_1A Receptor Occupancy by a Novel Antagonist, (R)-N-(2-Methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane Carboxamide (WAY-101405)

Abstract

5-Hydroxytryptamine (5-HT) 1A receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT 1A antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (K i ϭ 1.1 nM), selective (Ͼ100-fold), orally bioavailable, silent 5-HT 1A receptor antagonist (K B ϭ 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [3 H]WAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT 1A receptors in the rat cortex, with an ED 50 value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT 1A receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT 1A receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions. 5-Hydroxytryptamine (5-HT) exerts its diverse physiological and pharmacological effects through actions on multiple receptor subtypes (for review, see Hoyer et al., 2002), of which the 5-HT 1A receptor was the first described. The 5-HT 1A receptor has been implicated in numerous behavioral and physiological functions, including learning and memory. This receptor is located in brain regions associated with learning and memory, such as the hippocampus, frontal cortex, and entorhinal cortex (Chalmers and Watson, 1991), and the cellular and subcellular localization of the 5-HT 1A receptors allows for direct and indi- -100135, N-tert-butyl-3-[4-(2-methoxyphenyl)

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

“…The 5-HT1A antagonists WAY 100635 or WAY 100405 reversed the deleterious effects of scopolamine on SOR with a 60-min delay, and enhanced the performance of drug-naive rats with a 24-or 48-h delay (Hirst et al 2008;Pitsikas et al 2003). Pitsikas and colleagues found that WAY 100635 improved SOR when administered presample, post-sample or 30 min pre-choice, implying an effect of the drug on acquisition, consolidation and possibly retrieval (Pitsikas et al 2003).…”

“…The serotonergic system can also regulate cholinergic transmission (Shirazi-Southall et al 2002;Steckler and Sahgal 1995). A 5-HT6 antagonist reversed the effects of scopolamine (1 min; Woolley et al 2003) as did the 5-HT1A antagonist, WAY-101405 (Hirst et al 2008). WAY-101405 rescued a scopolamine-induced impairment with a 1-h delay and increased hippocampal acetylcholine release; a low dose also significantly improved SOR with a 48-h delay when coadministered with a low dose of donepezil.…”

The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

“…The effects of 5-HT 1A agents in NMDAR antagonist cognition models contrast with effects on cognition impaired by antimuscarinic agents and in normal rats. WAY100635 reversed the scopolamineinduced NOR deficit in rats and enhanced the retrieval of information in normal rats (Pitsikas et al 2003); another 5-HT 1A antagonist, WAY101405, has also been reported to improve scopolamine-induced deficits in the rat NOR model (Hirst et al 2008). It is possible, because of the heterogeneity which most likely is present in schizophrenia, that 5-HT 1A agonists or antagonists could each improve or impair cognition in different patients.…”

Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676

“…3 H]AZ10419369 (Maier et al, 2009) (Hirst et al, 2008). The time relative to AZD3676 administration (35 minutes for mice and guinea pigs and 60 minutes for rats) was selected based on the time profile for CNS exposure for the three species and guided by the physiologic response (reversal of agonistinduced hypothermia) recorded at different time points after AZD3676 administration as well as receptor-binding kinetics determined in vitro (unpublished observations).…”