Aporphines: A privileged scaffold in CNS drug discovery

Synthetic aporphine alkaloids are potential therapeutics for Leigh syndrome

“…The dopamine receptor affinities of synthetic aporphine alkaloids should be investigated in the future. The catechol groups at positions 10 and 11 of aporphine are responsible for the in vivo clearance and low bioavailability, and the pharmacokinetics may differ for the aporphine alkaloids found in this research 21 .…”

“…Apomorphine concentrations in the brain may be up to three-fold higher than those in plasma 20 . It and other aporphine alkaloids are known to have diverse pharmacological actions, not only at dopamine receptors, but also at serotonin, adrenergic alpha, and acetylcholine receptors 11 , 21 . Furthermore, apomorphine has been reported to exert antioxidant activity 21 , 22 , even before the discovery of ferroptosis 23 , a form of cell death caused by lipid peroxidation.…”

“…However, we recently reported that the anti-cell death effect of apomorphine is due to its anti-ferroptotic effect, regardless of its dopamine receptor agonist activities 10 , and we found that the synthetic aporphine alkaloids also possess anti-ferroptotic activity. Bulbocapnine, an aporphine alkaloid with a hydroxy group at position 11, has been reported to have in vitro CNS activity 21 along with nuciferine and several other naturally occurring aporphine alkaloids, and nuciferin has been reported to exert anti-ferroptotic activity 25 .…”

Natural Product-Inspired Dopamine Receptor Ligands

“…Comprising one of the largest groups of natural isoquinolines, aporphine alkaloids are widely distributed in flowering plant families, (e.g., Annonaceae, Aristolochiaceae, Berberidaceae, Canellaceae, Eupomatiaceae, Hernandiaceae, Lauraceae, Leguminosae, Magnoliaceae, Menispermaceae, Monimiaceae, Papaveraceae, Piperaceae, Ranunculaceae, Rhamnaceae, Saururaceae, and Symplocaceae families). − The tetracyclic backbone of naturally occurring aporphine alkaloids is typically decorated with substituents such as hydroxyl, methoxy, and methylenedioxy groups on the two aromatic rings. The aporphine alkaloids are a privileged scaffold in drug discovery, as natural aporphine alkaloids are reported to have a myriad of pharmacological activities including antioxidant, antitumor, anticonvulsant, antiplasmodial, antiparkinsonian, antimalarial, antiprotozoal, and cytotoxic effects …”

“…Apomorphine has undergone extensive SAR studies in efforts to optimize its selectivity, potency, and pharmacokinetic profile. The biphenyl unit, 11-hydroxy substitution, N -alkylation, and C-6α ( R ) configuration of aporphines are recognized as essential for dopaminergic activities. ,, N - n -Propyl substitution improves D 2 R activity, whereas an N -methyl substituent improves D 1 R activity. , This propyl effect of improving D 2 R activity can be applied to other dopaminergic molecules . The presence of a catechol group at the 1,2 position of the aporphine scaffold also favors dopamine receptor affinity, as exemplified by 1,2-demethylnuciferine ( 39 ) .…”