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Structure-based discovery of opioid analgesics with reduced side effects.

ABSTRACT: Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by ?-opioid-receptor (?OR) signalling through the ?-arrestin pathway or by actions at other receptors. Conversely, G-protein ?OR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the ?OR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent Gi activator with exceptional selectivity for ?OR and minimal ?-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle ?OR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

SUBMITTER: Manglik A

PROVIDER: S-EPMC5161585 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Structure-based discovery of opioid analgesics with reduced side effects.

Manglik Aashish A Lin Henry H Aryal Dipendra K DK McCorvy John D JD Dengler Daniela D Corder Gregory G Levit Anat A Kling Ralf C RC Bernat Viachaslau V Hübner Harald H Huang Xi-Ping XP Sassano Maria F MF Giguère Patrick M PM Löber Stefan S Da Duan Scherrer Grégory G Kobilka Brian K BK Gmeiner Peter P Roth Bryan L BL Shoichet Brian K BK

Nature 20160817 7619

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known ...[more]

PMID: 27533032

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Project description:BACKGROUND AND OBJECTIVES:Patients on hemodialysis frequently experience pain and may be particularly vulnerable to opioid-related complications. However, data evaluating the risks of opioid use in patients on hemodialysis are limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Using the US Renal Data System, we conducted a cohort study evaluating the association between opioid use (modeled as a time-varying exposure and expressed in standardized oral morphine equivalents) and time to first emergency room visit or hospitalization for altered mental status, fall, and fracture among 140,899 Medicare-covered adults receiving hemodialysis in 2011. We evaluated risk according to average daily total opioid dose (>60 mg, ?60 mg, and per 60-mg dose increment) and specific agents (per 60-mg dose increment). RESULTS:The median age was 61 years old, 52% were men, and 50% were white. Sixty-four percent received opioids, and 17% had an episode of altered mental status (15,658 events), fall (7646 events), or fracture (4151 events) in 2011. Opioid use was associated with risk for all outcomes in a dose-dependent manner: altered mental status (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.23 to 1.34; higher dose: hazard ratio, 1.67; 95% confidence interval, 1.56 to 1.78; hazard ratio, 1.29 per 60 mg; 95% confidence interval, 1.26 to 1.33), fall (lower dose: hazard ratio, 1.28; 95% confidence interval, 1.21 to 1.36; higher dose: hazard ratio, 1.45; 95% confidence interval, 1.31 to 1.61; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.03 to 1.05), and fracture (lower dose: hazard ratio, 1.44; 95% confidence interval, 1.33 to 1.56; higher dose: hazard ratio, 1.65; 95% confidence interval, 1.44 to 1.89; hazard ratio, 1.04 per 60 mg; 95% confidence interval, 1.04 to 1.05). All agents were associated with a significantly higher hazard of altered mental status, and several agents were associated with a significantly higher hazard of fall and fracture. CONCLUSIONS:Opioids were associated with adverse outcomes in patients on hemodialysis, and this risk was present even at lower dosing and for agents that guidelines have recommended for use.

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Structure-based discovery of opioid analgesics with reduced side effects.

Publications

Structure-based discovery of opioid analgesics with reduced side effects.

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