GPR88 is an orphan G protein-coupled receptor mainly expressed in the brain, whose endogenous ligand has not yet been identified. To elucidate GPR88 functions, our group has developed RTI-13951-33 (1b) as the first in vivo active GPR88 agonist, but its poor metabolic stability and moderate brain permeability remain to be further optimized. Here, we report the design, synthesis, and pharmacological characterization of a new series of RTI-13951-33 analogues with the aim of improving pharmacokinetic properties. As a result, we identified a highly potent GPR88 agonist RTI-122 (30a) (cAMP EC50 = 11 nM) with good metabolic stability (half-life of 5.8 h) and brain permeability (brain/plasma ratio of >1) in mice. Notably, RTI-122 was more effective than RTI-13951-33 in attenuating the binge-like alcohol drinking behavior in the drinking-in-the-dark paradigm. Collectively, our findings suggest that RTI-122 is a promising lead compound for drug discovery research of GPR88 agonists.

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 (2) and discovered dual agonists such as RTOXA-43 (40) with EC50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.

Background: A novel G-protein signalling-biased mu opioid peptide (MOP) receptor agonist, PZM21, was recently developed with a distinct chemical structure. It is a potent G(i/o) activator with minimal beta-arrestin-2 recruitment. Despite intriguing activity in rodent models, PZM21 function in non-human primates is unknown. The aim of this study was to investigate PZM21 actions after systemic or intrathecal administration in primates. Methods: Antinociceptive, reinforcing, and pruritic effects of PZM21 were compared with those of the clinically used MOP receptor agonists oxycodone and morphine in assays of acute thermal nociception, capsaicin-induced thermal allodynia, itch scratching responses, and drug self-administration in gonadally intact, adult rhesus macaques (10 males, six females). Results: After subcutaneous administration, PZM21 (1.0-6.0 mg kg(-1)) and oxycodone (0.1-0.6 mg kg-1) induced dose-dependent thermal antinociceptive effects (P<0.05); PZM21 was 10 times less potent than oxycodone. PZM21 exerted oxycodone-like reinforcing effects and strength as determined by two operant schedules of reinforcement in the intravenous drug self-administration assay. After intrathecal administration, PZM21 (0.03-0.3 mg) dose-dependently attenuated capsaicin-induced thermal allodynia (P<0.05). Although intrathecal PZM21 and morphine induced MOP receptor-mediated antiallodynic effects, both compounds induced robust, long-lasting itch scratching. Conclusions: PZM21 induced antinociceptive, reinforcing, and pruritic effects similar to clinically used MOP receptor agonists in primates. Although structure-based discovery of PZM21 identified a novel avenue for studying G-protein signalling-biased ligands, biasing an agonist towards G-protein signalling pathways did not determine or alter reinforcing (i.e. abuse potential) or pruritic effects of MOP receptor agonists in a translationally relevant non-human primate model.

The orexin system includes the neuropeptides orexin A and B and the cognate receptors of orexin-1 (OX1) and -2 (OX2) and has been indicated in a number of important physiological processes. It is generally accepted that the OX1 receptor is mainly involved in motivation and reward and the OX2 receptor in the modulation of sleep/wake cycle and energy homeostasis. A variety of OX1 selective antagonists (1-SORAs) have been disclosed in the literature and some of them have been evaluated as potential therapeutics for addiction treatment. In this review we summarize all OX1 antagonists reported thus far based on their core structure. Several dual orexin receptor antagonists (DORAs) and OX2 selective antagonist (2-SORAs) have also been recently evaluated in reward and addiction models. While DORAs may seem pharmacologically advantageous for alcohol addiction given the recent findings on the OX2 receptor in reward and alcohol consumption, 1-SORAs are the better options for other drugs of addiction such as cocaine due to the absence of the sedative effects inherently associated with dual antagonists.

PZM21 is a newly discovered G protein‐biased mu opioid peptide (MOP) receptor agonist which exerts antinociceptive effects with fewer side effects in rodents. The aim of this study was to determine the functional profile of systemic and spinal delivery of PZM21 in non‐human primates. Effects of PZM21 were compared with those of MOP agonists, such as oxycodone and morphine, in a series of behavioral assays established in rhesus monkeys (Macaca mutatta). Following systemic administration, PZM21 (1–6 mg/kg) and oxycodone (0.1–0.6 mg/kg) dose‐dependently produced antinociceptive effects against an acute noxious stimulus. Similar to a prescription opioid oxycodone, PZM21 produced reinforcing effects in primates under fixed ratio (FR30) and progressive‐ratio (PR) schedules of intravenous drug self‐administration. Following intrathecal administration, PZM21 (0.03–0.3 mg) and morphine (0.003–0.03 mg) dose‐dependently produced antinociceptive effects. Although intrathecal PZM21 has a slower onset for eliciting itch scratching activities, intrathecal PZM21 (0.3 mg) and morphine (0.03 mg) both elicited robust scratching responses lasting for more than 5 hours. In addition, intrathecal PZM21 (0.03–0.3 mg) dose‐dependently attenuated capsaicin‐induced thermal allodynia. Anti‐allodynic effects of intrathecal PZM21 or morphine could be blocked by a MOP receptor antagonist, naltrexone. Taken together, these pharmacological studies in primates indicate that PZM21 displays similar functional efficacy as an analgesic like clinically used MOP agonists, oxycodone and morphine. Although structure‐based discovery of PZM21 opens a new, exciting chapter for G protein‐biased MOP agonists, the abuse potential and pruritic effect of PZM21 are not significantly different from those of clinically used opioid analgesics in primates.Support or Funding InformationThe US‐PHS grants DA044775, DA032568, and DA040693.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

PZM21 (1) was recently reported as a biased agonist of the mu‐opioid receptor (MOR) with improved antinociceptive effects and reduced side effects compared with traditional opioid‐based analgesics. The original synthesis of PZM21 with the desired (S,S) configuration required the separation of a diastereomeric mixture in the final step by using chiral HPLC. A concise synthesis of 1 has now been developed in the enantiomeric pure form starting with commercially available l‐alanine and proceeding via a chiral aziridine as a key intermediate. The final product was obtained as the (S,S) diastereomer in seven steps in 22.5 % yield from l‐alanine. This synthetic strategy could be readily applied to the development of PZM21 analogues at the thiophenyl position.

Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency ( Ke = 5.7 nM) and selectivity (>1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability ( Papp = 14.7 × 10-6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).

SB612111 [(5S, 7S)-7-{[4-(2,6-dichlorophenyl) piperidin-1-yl] methyl}-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7] annulen-5-ol] is a potent and selective antagonist of the nociception/orphanin FQ peptide (NOP) receptor. In the process of synthesizing cis-SB612111 to support ongoing animal studies, several key steps of the published syntheses in the patent literature proceeded in low yields in our hands, particularly in the route to the key intermediate 4-(2,6-dichlorophenyl) piperidine, the reduction of 7-[4-(2,6-dichlorophenyl) piperidine-1-carbonyl]-1-methyl-6,7,8,9-tetrahydro-5H-benzo[7] annulen-5-one, the formation of (+/-)-6-methyl-12-oxatricyclo[8.2.1.0(2,7)] trideca-2,4,6-trien-11-one, and the final reductive amination between (+/-)-6-methyl-12-oxatricyclo[ 8.2.1.0(2,7)] trideca-2,4,6-trien-11-ol and 4-(2,6-dichlorophenyl) piperidine in the diastereoselective synthesis. We have thus explored various reaction conditions and successfully improved the yields for the necessary synthetic steps. We herein report our modified synthesis of SB612111 as the cis-diastereomers.

Selective antagonism of the orexin 1 (OX1) receptor has been proposed as a potential mechanism for treatment of drug addiction. We have previously reported studies on the structure-activity relationships of tetrahydroisoquinoline-based antagonists. In this report, we elucidated the respective role of the 6- and 7-substitutions by preparation of a series of either 6-substituted tetrahydroisoquinolines (with no 7-substituents) or vice versa. We found that 7-substituted tetrahydroisoquinolines showed potent antagonism of OX1, indicating that the 7-position is important for OX1 antagonism (10 c, Ke = 23.7 nM). While the 6-substituted analogs were generally inactive, several 6-amino compounds bearing ester groups showed reasonable potency (26 a, Ke = 427 nM). Further, we show evidence that suggests several compounds initially displaying insurmountable antagonism at the OX1 receptor are competitive antagonists with slow dissociation rates.

Selective blockade of the orexin-1 receptor (OX1) has been suggested as a potential approach to drug addiction therapy because of its role in modulating the brain's reward system. We have recently reported a series of tetrahydroisoquinoline-based OX1 selective antagonists. Aimed at elucidating structure-activity relationship requirements in other regions of the molecule and further enhancing OX1 potency and selectivity, we have designed and synthesized a series of analogues bearing a variety of substituents at the 1-position of the tetrahydroisoquinoline. The results show that an optimally substituted benzyl group is required for activity at the OX1 receptor. Several compounds with improved potency and/or selectivity have been identified. When combined with structural modifications that were previously found to improve selectivity, we have identified compound 73 (RTIOX-251) with an apparent dissociation constant (Ke) of 16.1 nM at the OX1 receptor and >620-fold selectivity over the OX2 receptor. In vivo, compound 73 was shown to block the development of locomotor sensitization to cocaine in rats.

Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. Aimed at studying these complexes, a series of bivalent CB1 and OX1 ligands combining SR141716 and ACT-078573 pharmacophores were designed, synthesized, and tested for activity against CB1 and OX1 individually and in cell lines that coexpress both receptors. Compound 20 showed a robust enhancement in potency at both receptors when coexpressed as compared to individually expressed, suggesting possible interaction with CB1-OX1 dimers. Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.

Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.

As a part of our program to develop OX1–CB1 bivalent ligands, we required a better understanding of the basic structure–activity relationships (SARs) of orexin antagonists. A series of SB-334867 analogues were synthesized and evaluated in calcium mobilization assays. SAR results suggest that the 2-methylbenzoxazole moiety may be replaced with a disubstituted 4-aminophenyl group without loss of activity and an electron-deficient system is generally preferred at the 1,5-naphthyridine moiety for OX1 antagonist activity. In particular, substitution of larger potential linkers such as n-hexyl provided compound 33 with equivalent activity at the OX1 receptor compared to the lead compound SB-334867. These compounds should be of value in the development of ligands targeting the orexin-1 receptor and its potential heterodimers.

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