Molecular mechanisms of fentanyl mediated β-arrestin biased signaling

Abstract

The development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, activates the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. We found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate a mechanism where the n-aniline ring of fentanyl mediates μOR βarrestin through a novel M153 "microswitch" by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles. Author SummaryThe global opioid crisis has drawn significant attention to the risks associated with over-use of synthetic opioids. Despite the public attention, and perhaps in-line with the profit-based incentives of the pharmaceutical industry, there is no public structure of mu-opioid receptor bound to fentanyl or fentayl derivatives. A publicly available structure of the complex would allow open-source development of safer painkillers and synthetic antagonists. Current overdose antidotes, antagonists, require natural products in their synthesis which persists a sizable barrier to market and develop better antidotes. In this work we use advance molecular dynamics techniques to obtain the bound geometry of mu-opioid receptor with fentanyl (and derivatives). Based on our in-silico structure, we synthesized and tested novel compounds to validate our predicted structure. Herein we report the bound state of several dangerous fentanyl derivatives and introduce new derivatives with signaling profiles that may lead to lower risk of respiratory depression.

Low intrinsic efficacy alone cannot explain the improved side effect profiles of new opioid agonists

“…In a recent example, similar BRET-based studies were elegantly employed for similar analysis by Ehrlich et al,42 investigating ligand bias at the mu opioid receptor where they demonstrate diverse signaling profiles of oliceridine, PZM21 and buprenorphine in neurons. In time, the value of these cellular readouts as predictors of agonist function may be supported by detecting state-dependent structural conformations of MOR induced by biased ligands binding to the receptor[43][44][45] . This does not make their pharmacology less remarkable not does it disprove the hypothesis that ligands may demonstrate active state selectivity.…”

Estudo teórico de opioides sintéticos no contexto das novas substâncias psicoativas

“…Seu primeiro uso médico foi em cirurgias como um anestésico intravenoso e hoje é um dos medicamentos mais utilizados para o tratamento de dores pós-operatórias, severas e crônicas em todo o mundo 2 . Seu efeito farmacêutico é produzido pela atividade agonista com o receptor µ-opioide do sistema nervoso central 3,4 . Estima-se que o fentanil seja em torno de 100 vezes mais potente que a morfina, e cerca de 30-50 vezes mais potente que a heroína 3 .…”

“…A repetida administração do fentanil leva à dependência e tolerância, e o seu simples uso gera sintomas como sonolência, euforia, constrição das pupilas e depressão respiratória. Este último efeito é o principal causador das mortes por overdose, uma vez que leva à parada respiratória e ao edema pulmonar 4,7 . O uso do fentanil também pode causar efeitos colaterais como náusea, tontura e vômito, e sintomas de abstinência como ansiedade, câimbra, dores nos ossos e diarreia 8 .…”

“…Em 2017, dentre os NPFs que surgiram, o metoxiacetilfentanil e o ciclopropilfentanil foram os que mais contribuíram para a epidemia 18 , sendo que aproximadamente 33% das mortes por overdose naquele ano tiveram algum opioide envolvido 20 . Além disso, o número de overdose aumentou dez vezes de 2013 a 2017 nos EUA 4 . O acetilfentanil foi o principal análogo do fentanil que surgiu em 2018 20 , e comparando as mortes por fentanil entre 2016 e 2018, observou-se um aumento de 25% 20 .…”