Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use

Abstract

Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were initially associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA) suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders. In this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioral and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice

“…These results are in line with a wide range of studies indicating that the ORX system is critically involved in stimuli or outcomes that produce strong degrees of motivated behavior (Borgland et al, 2009; Merlo Pich and Melotto, 2014). These studies led to our proposal that a major function of the ORX system is in motivational activation (Mahler et al, 2014).…”

“…This compound has slightly higher selectivity for OX1R vs. OX2R than SB-334867 (~79-fold) and displays none of the significant off-target binding shown by SB-334867 (Gotter et al, 2012). This compound has also been shown to decrease cocaine conditioned place preference and compulsive eating (though not homeostatic or hedonic eating), in the absence of any influence on arousal (Gozzi et al, 2013; Merlo Pich and Melotto, 2014; Piccoli et al, 2012). Based on these results, we predicted that highly selective OX1R antagonism would have minimal influences on hedonic alcohol or sucrose consumption, but would strongly impact dependence-based alcohol drinking, which has been shown to exhibit elements of compulsivity (Vendruscolo et al, 2012; Vendruscolo and Roberts, 2014).…”

“…Also of note, SB-334867 did not alter acquisition or expression of alcohol-induced conditioned place preference (Voorhees and Cunningham, 2011). For these reasons, we tested the influence of the highly selective OX1R antagonist GSK1059865 (Gozzi et al, 2013; Merlo Pich and Melotto, 2014; Piccoli et al, 2012). This compound has slightly higher selectivity for OX1R vs. OX2R than SB-334867 (~79-fold) and displays none of the significant off-target binding shown by SB-334867 (Gotter et al, 2012).…”

Synthesis of [11C]MK-1064 as a new PET radioligand for imaging of orexin-2 receptor

“…5 The available experimental evidences strongly support that OX2R plays a key role in motivation, arousal and sleep-wake regulation, and is associated with sleep disorders, irregularities in central vestibular motor control, feeding and gastrointestinal disorders and drug abuse. 6 Although OX1R is thought to regulate sleep-wakefulness and energy homeostasis, particularly food intake, the therapeutic potential of selective antagonism of OX1R is still under evaluation. 6 Orexin receptor is an interesting therapeutic target, and many selective orexin receptor antagonists have been developed.…”

“…6 Although OX1R is thought to regulate sleep-wakefulness and energy homeostasis, particularly food intake, the therapeutic potential of selective antagonism of OX1R is still under evaluation. 6 Orexin receptor is an interesting therapeutic target, and many selective orexin receptor antagonists have been developed. 3,4 However, the in vivo selectivity, distribution and involvements of OX1R and OX2R in the pathophysiology of orexin-related disorders are not fully understood.…”