Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids

Abstract

Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.

Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

“…The oral bioavailability of mitragynine in dogs was found to be 2.5-and 4.2fold higher than that of the oral bioavailability of mitragynine in rats [27,33]. A CYP3A-mediated oxidative metabolite of mitragynine, 7-hydroxymitragynine, has shown potent mu-opioid (K i , 7.2 ± 0.9 nM) activity [11,36]. Mitragynine appears to be a promising treatment for opioid self-administration without any abuse or addiction potential [15,16].…”

“…Mitragynine showed similar absorption across species as the C max occurred within 2 h postdose in rats, dogs, and humans [21,27,33]. Opioid receptor-mediated delayed gastric emptying and/or absorption through multiple sites in the gastrointestinal tract could be potential causes for the multiple peaks [11,34]. Also, the insoluble compound may be solubilized by bile salts and phospholipid release in the bile, and it may be responsible for the C max2 .…”

“…Mitragynine appears to be a promising treatment for opioid self-administration without any abuse or addiction potential [15,16]. However, 7-hydroxymitragynine exhibits a 22.5-fold increase in binding affinity at the mu-opioid receptor compared to mitragynine (K i , 161.0 ± 10.0 nM) [11], which raises concerns of opioid-mediated abuse or addiction potential. Therefore, plasma levels of 7-hydroxymitragynine were also measured in the test samples.…”

“…Several studies have suggested that mitragynine and products containing mitragynine have analgesic, anti-inflammatory, antipyretic, antidiarrheal, euphoric, antidepressant, and anxiolytic effects [5][6][7][8][9]. Mitragynine binds to opioid (mu and kappa), alpha-adrenergic (α 1A , α 1B , α 1D , α 2A , α 2B , and α 2C ), adenosine (A 2a ), dopamine (D 2 ), and serotonin (5-HT 2C , and 5-HT 7 ) receptors [10,11]. Mitragynine is a mu-opioid receptor agonist with a moderate affinity (K i , 161 ± 10 nM), but it is also a kappa-opioid antagonist (K i , 198 ± 30 nM) [11].…”

“…Mitragynine binds to opioid (mu and kappa), alpha-adrenergic (α 1A , α 1B , α 1D , α 2A , α 2B , and α 2C ), adenosine (A 2a ), dopamine (D 2 ), and serotonin (5-HT 2C , and 5-HT 7 ) receptors [10,11]. Mitragynine is a mu-opioid receptor agonist with a moderate affinity (K i , 161 ± 10 nM), but it is also a kappa-opioid antagonist (K i , 198 ± 30 nM) [11]. It is a partial and biased agonist at the mu-opioid receptor with an E max of approximately 40 % that of DAMGO [(D-Ala 2 , N-MePhe 4 , Gly-ol 5 )-enkephalin] in assays of G-protein activation, and has almost no effect in β-arrestin-2 assays [12].…”