Discovery of indole alkaloids with cannabinoid CB1 receptor antagonistic activity

Identification of a Potent and Selective Cannabinoid CB1Receptor Antagonist fromAuxarthron reticulatum

“…Only very recently, the first natural alkaloids with CB 1 -antagonistic activity isolated from the plant Voacanga africana were described. 19 Functional studies indicate that compound 1 appears to be a neutral competitive antagonist, as no increased cAMP levels could be detected in cAMP accumulation assays. There is evidence that neutral antagonists may be preferable over inverse agonists when used as drugs, because they do not alter basic activity arising from spontaneous receptor signaling and, thus, may cause less side effects.…”

Alkaloids

“…249,250 In fact, the sigma-1 (σ1) receptor agonist PRE-084 at a dose of 0.1 μg/g abrogated neuronal insults induced by the glutamatergic agonist ibotenate by inhibition of microglial activation and protection of neurons against glutamate insults with inhibition of caspase 3. 259,260 In fact, the CB1 receptor antagonist SR141716A at a dose of 1 mg/kg protected rodents against dementia induced by 16 nmol of β-amyloid (Aβ 25-35 ) peptide or 800 pmol of β-amyloid (Aβ 1-42 ) peptide. Increasing evidence supports the notion that ibogans are nicotinic receptor antagonists, as shown with ibogaine, which antagonized α3β4 nicotinic receptors with a K d value equal to 0.4 μM, 252 as well as α1β1γδ nicotinic receptors with an IC 50 value equal to 17 μM 253 and inhibited the enzymatic activity of AChE with an IC 50 value equal to 520 μM.…”

“…247 Sigma-1 (σ1) endoplasmic reticulum receptors are of particular interest based on the fact that a cytoplasmic Ca 2+ increase in neurons results in σ1-Bip dissociation and the release of σ1 in the cytoplasm, 248 which contravenes β-amyloid (Aβ 25-35 ) peptide-induced apoptosis. 259 implying that the C3-C6 ether moiety is favorable for activity. 251 It therefore seems reasonable to consider ibogan alkaloids as a vast source of untapped sigma-1 (σ1) agonists awaiting further studies for the treatment of AD and other neurodegenerative conditions.…”

Small Molecules from Nature Targeting G-Protein Coupled Cannabinoid Receptors: Potential Leads for Drug Discovery and Development

“…Voacamine, 3,6-oxidovoacangine, and 5-hydroxy-3,6-oxidovoacangine are the indole alkaloids isolated from methanolic extract of root bark of Voacanga africana , a tropical African tree. Several compounds have been isolated and screened for the cannabinoid activity in Aequorin/GPCR cell-based Ca 2+ functional assay using CP55,940 or rimonabant as a positive control for cannabinoid receptors ligands [ 111 ]. These compounds exhibited potent CB 1 receptor antagonist activity in a concentration-dependent manner compared to rimonabant, whereas the other coexisting alkaloids, such as voacangine, vobasine, and tabersonine, fail to exhibit any CB receptor mediated activity.…”