Research Projects

Chemistry and Pharmacology of Kratom alkaloids

Mitragyna speciosa plant also known, as kratom is a rich source of natural products with opioid activity. Kratom leaves have been consumed by Malayans of South-East Asia for centuries and is recreationally used by 2-3 million Americans. Nearly 40 alkaloids are present in kratom with mitragynine (1-2%) being the major alkaloid (Fig. 1), which show opioid activity. Another semi-synthetic alkaloid derived from mitragynine named mitragynine pseudoindoxyl in this series has potent opioid mediated analgesia while showing opioid functional selectivity in vivo (Fig. 3A-E). We recently showed the analgesic actions of kratom’s major alkaloid mitragynine can be explained by its metabolic conversion to 7OH mitragynine (Fig. 2). The molecular mechanisms of how kratom alkaloids exhibit their biological activity (analgesia and/or abuse) is still unknown. Kratom alkaloids (synthetic and semi-synthetics) thereby offer exciting opportunities to discover probes to understand opioid action, novel opioid drug targets and drugs for treatment of both pain and substance abuse disorders. We are interested in the structure activity relationships on all three templates-mitragynine, 7OH mitragynine and mitragynine pseudoindoxyl.

Chemistry and Pharmacology of Kratom alkaloids example 1
Fig.1 Structures of the kratom based alkaloids
Chemistry and Pharmacology of Kratom alkaloids example 2
Fig.2 Metabolism as a mediator of Kratom analgesia

Chemistry and Pharmacology of Kratom alkaloids example 2
Fig.3A-D. Pharmacology of MP and 3E. SAR efforts on MP

J Med Chem 2016, 59(18):8381-97
Nature  2018, 553(7688):286-288
ACS Central Sci 2019, 5(6), 992-1001.

Structural based design of G-protein biased ligands

Synthesis of opioid probes which target the G-protein biased signaling pathways instead of βarrestin-2 biased signaling pathways have been proposed in the opioid field to separate opioid induced physiological responses like constipation and respiratory depression from analgesia. (Rankovic et al., Bioorg Med Chem Lett. 2016 Jan 15;26(2):241-250). Studies from herkenorin, TRV130, mitragynine(s), SR17018 and PZM21 coupled with studies of morphine in βarrestin-2 KO mice suggest opioid functional selectivity can be achieved in preclinical rodent models. Our goal is to identify functional hot spots in the receptor responsible for recruitment of βarrestin-2. We will utilize computational chemistry, chemical synthesis, structure based design and site-directed mutagenesis to identify amino residues and/or transmembrane pockets in the receptor which dictate engagement with βarrestin-2. Ligands identified as biased will then be characterized in vivo for their physiological responses like analgesia, locomotor effect, respiratory depression and conditional place preference.

Cyclohexane ring-C chair boat conformations dictate G-protein bias at mu opioid receptor
Cyclohexane ring-C chair boat conformations dictate G-protein bias at mu opioid receptor

Cell 2018, 172(1-2):55-67.
Neuropharmacology 2019, pii: S0028-3908(18)30757-3.
ACS Chem Neuro 2015, 6(11):1813-24.

Targeting opioid heteromers and allosteric targets

It has been shown that upon activation, the opioid receptors form physiologically relevant dimers which are necessary for maturation, trafficking and downstream signaling. A previous study identified CYM51010 as a small molecule probe that selectively activates μOR-δOR heteromers and exhibits antinociception similar to morphine with reduced antinociceptive tolerance (Gomes et al, PNAS 2013). Since CYM51010 exhibits conditional place preference and respiratory depression in mice, possibly because it retains a moderate efficacy at homomeric μOR in functional assays and is still β arrestin-2 biased, ligands exclusively selective for μOR-δOR heteromers are needed. We are working on carfentanyl amide based opioid templates as novel G-protein biased modulators of μOR-δOR heteromers with a greater selectivity over the homomeric μOR and δOR (when compared to that of CYM51010).

Targeting mu-delta opioid heteromers example 1
ACS Chem Neuro 2015, 6(9):1570-7.
Targeting mu-delta opioid heteromers example 1

Multicomponent reactions and CNS targets

Multicomponent reactions (MCRs) are convergent reactions, in which three or more starting materials react to form a single product, where all or most of the atoms contribute to the newly formed product. The extreme variety of products that can be achieved through the reaction of readily available reagents as well as their one-pot nature and high atom efficiency make MCRs suitable for the synthesis of highly diverse drug-like libraries. We have utilized the isocyanide based Ugi MCR to access diverse heterocycles with activity at CNS targets.

Multicomponent reaction example 1
A MCR with aminophenols
Org. Lett., 2014, 16 (6), pp 1668–1671
Multicomponent reaction example 2
A MCR with amino acids
Eur J Med Chem 2019,164, 241-251


University of Florida
Jay McLaughlin, PhD

Hungarian Academy of Sciences
Attila Borics, PhD
Sandor Hosztafi, PhD

Mount Sinai School of Medicine
Marta Filizola, PhD
Lakshmi Devi, PhD

Stanford University
Vijay Pande, PhD

Columbia University
Jonathan Javitch, PhD

Dalibor Sames, PhD

Long Island University
Grace Rossi, PhD

Rutgers University
John Pintar, PhD

Victoria University, NZ
Bronwyn Kivell PhD

Purdue University
Richard Van Rijn, PhD

Bridge Institute, USC
Vsevolod Katritch, PhD
Saheem Zaidi, PhD

Washington University

Bryan Roth, MD PhD

Funding Sources

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