(-)-Isocorypalmine

FEBS Lett . 2014 Jan 3;588(1):198-204.

Cloning and characterization of canadine synthase involved in noscapine biosynthesis in opium poppy[Pubmed: 24316226]

Abstract Noscapine biosynthesis in opium poppy is thought to occur via N-methylcanadine, which would be produced through 9-O-methylation of (S)-scoulerine, methylenedioxy bridge formation on (S)-tetrahydrocolumbamine, and N-methylation of (S)-canadine. Only scoulerine 9-O-methyltransferase has been functionally characterized. We report the isolation and characterization of a cytochrome P450 (CYP719A21) from opium poppy that converts (S)-tetrahydrocolumbamine to (S)-canadine. Recombinant CYP719A21 displayed strict substrate specificity and high affinity (Km=4.63±0.71 μM) for (S)-tetrahydrocolumbamine. Virus-induced gene silencing of CYP719A21 caused a significant increase in (S)-tetrahydrocolumbamine accumulation and a corresponding decrease in the levels of putative downstream intermediates and noscapine in opium poppy plants. Keywords: BIA; Benzylisoquinoline alkaloid; CID; CPR; CYP; Cytochrome P450; ESI; GAPDH; LC–MS/MS; Methylenedioxy bridge; Noscapine biosynthesis; Papaver somniferum; SOMT; TNMT; TRV; VIGS; Virus-induced gene silencing; benzylisoquinoline alkaloid; collision-induced dissociation; cytochrome P450; cytochrome P450 reductase; electrospray ionization; glyceraldehyde 3-phosphate dehydrogenase; liquid chromatography–tandem mass spectrometry; scoulerine 9-O-methyltransferase; tetrahydroprotoberberine N-methyltransferase; tobacco rattle virus; virus-induced gene silencing.

Drug Alcohol Depen., 2013, 133(2):693- 703.

L-isocorypalmine reduces behavioral sensitization and rewarding effects of cocaine in mice by acting on dopamine receptors.[Pubmed: 24080315 ]

We previously reported isolation of l-isocorypalmine (l-ICP), a mono-demethylated analog of l-tetrahydropalmatine (l-THP), from the plant Corydalis yanhusuo. Here we characterized its in vitro pharmacological properties and examined its effects on cocaine-induced behaviors in mice.
METHODS AND RESULTS:
Receptor binding, cAMP and [(35)S]GTPγS assays were used to examine pharmacological actions of l-ICP in vitro. Effects of l-ICP on cocaine-induced locomotor hyperactivity and sensitization and conditioned place preference (CPP) in mice were investigated. HPLC was employed to analyze metabolites of l-ICP in mouse serum. Among more than 40 targets screened, l-ICP and l-THP bound only to dopamine (DA) receptors. l-ICP was a high-affinity partial agonist of D1 and D5 receptors and a moderate-affinity antagonist of D2, D3 and D4 receptors, whereas l-THP bound to only D1 and D5 receptors, with lower affinities than l-ICP. At 10mg/kg (i.p.), l-ICP inhibited spontaneous locomotor activity for a shorter time than l-THP. Pretreatment with l-ICP reduced cocaine-induced locomotor hyperactivities. Administration of l-ICP before cocaine once a day for 5 days reduced cocaine-induced locomotor sensitization on days 5 and 13 after 7 days of withdrawal. Pretreatment with l-ICP before cocaine daily for 6 days blocked cocaine-induced CPP, while l-ICP itself did not cause preference or aversion. HPLC analysis showed that l-ICP was the main compound in mouse serum following i.p. injection of l-ICP.
CONCLUSIONS:
l-ICP likely acts as a D1 partial agonist and a D2 antagonist to produce its in vivo effects and may be a promising agent for treatment of cocaine addiction.