Kratom (Mitragyna speciosa) is a tropical tree from Southeast Asia that produces opioid- and stimulant-like effects.¹ It is used as a self-treatment for pain and as an energy booster. Mitragynine is the major indole alkaloid in kratom and is thought to be primarily responsible for the pharmacological effects of kratom.^1,2Mitragynine shows no structural resemblance to traditional morphine-type compounds, and although it binds to opioid receptors, it also binds several other targets, resulting in very distinct signaling properties and physiological effects compared to therapeutic opioid analgesics. Structure-activity relationship (SAR) investigations of mitragynine have been primarily focused around the indole-nucleus of the scaffold. Previous literature reports provide a basic SAR of mitragynine with respect to the substitutions on the saturated rings of mitragynine (mostly at C9, C11, and C12 positions).^3,4Krugel et al. demonstrated that unsaturated beta-methoxy acrylate is a key moiety of mitragynine for binding with the MOR, therefore this part of the molecule has been kept integral throughout most of the studies in literature.^3,4The present work aimed at developing novel molecules derived from mitragynine which can mimic its properties by chemically modifying the ester portion of the beta-methoxy acrylate to the bioisosteric amide functional group. Compounds were synthesized and screened separately at opioid and adrenergic receptors using radioligand binding assays. Among the sixteen synthesized analogs, most of the compounds displayed promising results. Two compounds, SUSM-522 and SUSM-523, exhibited high affinity for MOR with K_i values of 67.8±7.0 and 81.9±9.0 nM, respectively and approximately ten-fold higher than mitragynine (709.0±91.2 nM). The adrenergic receptor binding of SUSM-501 at alpha-2A (K_i, 1810±91.2 nM) and alpha-2C (K_i, 410±110 nM) receptors higher to mitragynine at alpha-2A (K_i, 4090±273 nM) and alpha-2C (K_i, 4040±417 nM) receptors. The details of synthesis, SAR, and metabolic stability of novel amide analogs will be presented and compared with mitragynine.

Lance McMahon

Appearances