PT  - JOURNAL ARTICLE
AU  - Soumen Chakraborty
AU  - Jeffrey F. DiBerto
AU  - Abdelfattah Faouzi
AU  - Sarah M. Bernhard
AU  - Anna M. Gutridge
AU  - Steven Ramsey
AU  - Yuchen Zhou
AU  - Davide Provasi
AU  - Nitin Nuthikattu
AU  - Rahul Jilakara
AU  - Melissa N.F. Nelson
AU  - Wesley B. Asher
AU  - Shainnel O. Eans
AU  - Lisa L. Wilson
AU  - Satyanarayana M Chintala
AU  - Marta Filizola
AU  - Richard M. van Rijn
AU  - Elyssa B. Margolis
AU  - Bryan L. Roth
AU  - Jay P. McLaughlin
AU  - Jonathan A. Javitch
AU  - Tao Che
AU  - Susruta Majumdar
TI  - A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects
AID  - 10.1101/2021.04.22.440994
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.22.440994
4099  - http://biorxiv.org/content/early/2021/04/22/2021.04.22.440994.short
4100  - http://biorxiv.org/content/early/2021/04/22/2021.04.22.440994.full
AB  - Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom’s natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal β-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and β-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl (SC11), methyl (SC12), 3’-furanyl (SC13), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.Competing Interest StatementThe authors declare the following competing financial interest(s): S.M. is a co-founder of Sparian Inc and J.A. J. is a co-founder of Kures. Both SM and JAJ are inventors on patent applications related to mitragynine analogs, which may lead to royalties or other licensing revenues from future commercial products.