Magnolia-derived alkaloids as dual DAT inhibitors/5-HT1A agonists Anonaine, a benzylisoquinoline alkaloid, has been detected in Magnolia grandiflora and found in many species of Annonacae, including Annona reticulata (0.12%). Anonaine displays antitumour, vasorelaxation, antioxidative, antiparasitic and antimicrobial effects, as well as having an effect on the central nervous system (inhibiting dopamine reuptake and acting as an agonist at 5-HT1ARs along with α1-adrenoceptor antagonism). Other plants containing anonaine [1]: Goniothalamus australis aerial parts of Annona cherimola bark of Annona salzmannii Michelia champaca (Magnolia) Liriodendron tulipifera leaves of Michlia alba (Magnolia) Magnolia grandiflora Stephania yunnanensis bark of Guatteria hispida Fissistigma latifolium Polyalthia longifolia Rollinia leptopetala fruit of Annona muricata Annona cherimolia Annona squamosa 1 Artabotrys maingayi Chamanthera dependens Nelumbo lutea In M. grandiflora : The flower contains liriodenine, anonaine, dehydroremerine (0.52% total alkaloids) Leaf from the flowering plant contains anonaine, remerine, liriodenine and rutine (0.54 % total alkaloids) It also contains essential oils 0.58 % ( − )-anonaine has good selectivity for 3H-dopamine uptake. The affinity of ( − )-anonaine at dopamine D1 3H-SCH 23390 and D2 3H-raclopride binding sites was low ⦁ 5 - 10mg / kg in mice exhibited antidepressant activity Anonaine, the principle leaf alkaloid displayed affinity of 0.8 μM, the same order as the reference compounds nomifensine (0.2 μM), but more potent than amineptine and dexamphetamine at DAT. The oxoaporphine liriodenine was virtually devoid of activity as a dopamine reuptake inhibitor. It also has affinity for 5-HT1A and α1 adrenergic receptor affinity. Although not overly potent, studies suggest they are α1A antagonists, as is demonstrated by the vasorelaxant responses. One study has shown that a unique alkaloid, ( − )-anonaine, liriodenine, and nornuciferine are the main constituents of the aerial parts of Annona cherimola . These main constituents produced antidepression-like effects due to the 5-HT1A receptor agonistic activity of ( − )- anonaine and nornuciferine. These results indicate that ( − )-anonaine displays dopamine uptake inhibitory and 5-HT1A agonistic activity with anti-depressant activity. Interestingly, despite relatively potent DAT inhibition, the longer-term net effect of (-)- anonaine on dopamine seems to be decreased dopamine content, potentially via interfering with dopamine biosynthesis via tyrosine hydroxylase [2]. This may be why, contrary to psychostimulant effects, the more tradtional use and effect of plants containing (-)- anonaine doesn't fit in line with the more classical dopamine transporter inhibition effect. Also, caution is required as some studies have noted potential neurotoxicity from 2 Annonaceae extracts, some reports of atypical parkinsonism being noted [1] The Pharmacological Activities of (−)-Anonaine https://doi.org/10.3390% 2Fmolecules18078257 [2] Lee JJ, Jin CM, Kim YK, Ryu SY, Lim SC, Lee MK. Effects of anonaine on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells. Molecules. 2008 Feb 27;13(2):475-87 https://doi.org/10.3390%2Fmolecules13020475 3