κ opioid receptor (KOR) antagonists are potential pharmacotherapies for the treatment of migraine and stress-related mood disorders including depression, anxiety and drug abuse, thus the development of novel KOR antagonists with an improved potency/selectivity profile and medication-like duration of action has attracted the interest of the medicinal chemistry community. In this paper, we describe the discovery of 1-(6-ethyl-8-fluoro-4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidin-4 amine (CYM-53093, BTRX-335140) as a potent and selective KOR antagonist, endowed with favorable in vitro ADMET and in vivo pharmacokinetic profiles and medication-like duration of action in rat pharmacodynamic experiments. Orally administered CYM-53093 showed robust efficacy in antagonizing KOR agonist-induced prolactin secretion and in tail-flick analgesia in mice. CYM-53093 exhibited a broad selectivity over a panel of off-target proteins. This compound is in Phase 1 clinical trials for the treatment of neuropsychiatric disorders wherein dynorphin is thought to contribute to the underlying pathophysiology.

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.

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19Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of 20 stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR 21 agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to 22 aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic 23 approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain 24 slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, 25 BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently 26 reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and 27 BTRX-395750 fully blocked U-69,593 currents (IC 50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively).28 JNJ-67953964 showed an IC 50 of 0.3 ± 1.3 nM. PF-04455242 (IC 50 = 19.6 ± 16 nM) exhibited 29 partial antagonist activity (~60% maximal blockade). In 50% of neurons, 1 M PF-04455242 30 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not 31 affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO 32 or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked 33 DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) 34 rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we 35 show electrophysiological evidence of key differences amongst KOR antagonists that could 36 impact their therapeutic potential and have not been observed using recombinant systems. The 37 results of this study demonstrate the value of characterizing compounds in native neuronal tissue 38 and within disorder-relevant circuits implicated in neurobehavioral disorders. Introduction 40One of the major challenges in drug development is predicting whole animal responses 42 indicate that the effect of drugs on G protein coupled receptor function in situ in brain tissue is not 43 reliably predicted from results in expression systems [3][4][5][6][7][8]. Therefore pharmacological 44 characterizations made in brain tissue likely relate better to behavioral outcomes than those made 45 in cell-based expression assays. 46Interest in the kappa opioid receptor (KOR) as a target for therapeutic development has 47 been growing consistently as clinical and preclinical studies have identified its role in aversive 48 behavioral states. KOR agonists produce profound adverse effects in humans, specifically 49 fatigue, sedation, confusion, impaired concentration, and anxiety. Furthermore at higher 50 concentrations visual and auditory hallucinations and feelings of depersonalization have been 51 reported [9,10]. Homologous effects have been described in animal models (reviewed in [11]). 52 Finally, blockade or genetic deletion of the KOR significantly reduces aversive responses to stress 53 [12-14], drug withdrawal [15-17], and pain [18], and has antidepres...

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