Opioid activity of alkaloids extracted from Picralima nitida (fam. Apocynaceae)

Extracts of the seeds of Picralima nitida (fam. Apocynaceae) have been reported to have opioid analgesic activity. In this investigation, isolated tissue bioassays and radioligand binding assays have been used to determine the opioid activity of five alkaloids—akuammidine, akuammine, akuammicine, akuammigine and pseudoakuammigine—extracted from the seeds of P. nitida. Akuammidine showed a preference for μ-opioid binding sites with K i values of 0.6, 2.4 and 8.6 μM at μ-, δ- and κ-opioid binding sites, respectively. The agonist actions of akuammidine in the mouse-isolated vas deferens were antagonised by naloxone and the μ-opioid receptor selective antagonist d-Phe–Cys–Tyr– d-Trp–Orn–Thr–Pen–Thr–NH 2 (CTOP) confirming an action at μ-opioid receptors. In contrast, akuammine also showed highest affinity for μ-opioid binding sites ( K i 0.5 μM) but was an antagonist at μ-opioid receptors with a p K B of 5.7 against the selective μ-opioid receptor agonist [ d-Ala 2,MePhe 4,Gly-ol 5]enkephalin (DAMGO). Akuammicine has the highest affinity for κ-opioid binding sites ( K i 0.2 μM) and was a full agonist at κ-opioid receptors in the guinea pig ileum preparation but a partial κ-opioid receptor agonist in the vasa deferentia of the mouse and the rabbit. Akuammigine and pseudoakuammigine showed little or no efficacy in the opioid bioassays. None of the alkaloids had significant activity for opioid receptor-like binding sites (ORL 1-binding sites) with K i values ≫10 μM. These data show that some alkaloids extracted from the medicinal plant P. nitida possess varying degrees of agonist and antagonist activity at opioid receptors but possess neither high affinity nor selectivity for μ-, δ- or κ-opioid receptors or the ORL 1-receptor.