Worldwide, there are plants known as psychoactive plants that naturally contain psychedelic active components. They have a high concentration of neuroprotective substances that can interact with the nervous system to produce psychedelic effects. Despite these plants' hazardous potential, recreational use of them is on the rise because of their psychoactive properties. Early neuroscience studies relied heavily on psychoactive plants and plant natural products (NPs), and both recreational and hazardous NPs have contributed significantly to the understanding of almost all neurotransmitter systems. Worldwide, there are many plants that contain psychoactive properties, and people have been using them for ages. Psychoactive plant compounds may significantly alter how people perceive the world.
1. J Med Chem. 2023 Mar 9;66(5):3312-3326. doi: 10.1021/acs.jmedchem.2c01707. Epub 2023 Feb 24. Modified Akuamma Alkaloids with Increased Potency at the Mu-opioid Receptor. Hennessy MR(1), Gutridge AM(2), French AR(2)(3), Rhoda ES(2), Meqbil YJ(2), Gill M(1), Kashyap Y(1), Appourchaux K(4), Paul B(4), Wang ZJ(1)(3), van Rijn RM(2)(5)(6)(7), Riley AP(1). Author information: (1)Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois 60612, United States. (2)Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States. (3)Departments of Neurology and Bioengineering, University of Illinois Chicago, Chicago, Illinois 60612, United States. (4)Center for Clinical Pharmacology, University of Health Sciences & Pharmacy at St. Louis and Washington University School of Medicine, St. Louis, Missouri 63110, United States. (5)Purdue Institute for Drug Discovery, West Lafayette, Indiana 47907, United States. (6)Purdue Institute for Integrative Neuroscience, West Lafayette, Indiana 47907, United States. (7)Purdue Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, Indiana 47907, United States. Akuammine (1) and pseudoakuammigine (2) are indole alkaloids found in the seeds of the akuamma tree (Picralima nitida). Both alkaloids are weak agonists of the mu opioid receptor (μOR); however, they produce minimal effects in animal models of antinociception. To probe the interactions of 1 and 2 at the opioid receptors, we have prepared a collection of 22 semisynthetic derivatives. Evaluation of this collection at the μOR and kappa opioid receptor (κOR) revealed structural-activity relationship trends and derivatives with improved potency at the μOR. Most notably, the introduction of a phenethyl moiety to the N1 of 2 produces a 70-fold increase in potency and a 7-fold increase in selectivity for the μOR. The in vitro potency of this compound resulted in increased efficacy in the tail-flick and hot-plate assays of antinociception. The improved potency of these derivatives highlights the promise of exploring natural product scaffolds to probe the opioid receptors. DOI: 10.1021/acs.jmedchem.2c01707 PMCID: PMC10037270 PMID: 36827198 [Indexed for MEDLINE] 2. J Nat Prod. 2021 Jan 22;84(1):71-80. doi: 10.1021/acs.jnatprod.0c01036. Epub 2020 Dec 16. Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids. Creed SM(1), Gutridge AM(2), Argade MD(1), Hennessy MR(1), Friesen JB(3), Pauli GF(3), van Rijn RM(4), Riley AP(1). Author information: (1)Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States. (2)Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States. (3)Department of Pharmaceutical Sciences and Pharmacognosy Institute, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States. (4)Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue Institute for Drug Discovery, Purdue Institute for Integrative Neuroscience, Purdue Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, Indiana 47907, United States. The seeds of the akuamma tree (Picralima nitida) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine (1), pseudo-akuammigine (3), akuammicine (4), akuammiline (5), and picraline (6), were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed in vitro investigations revealed 4 to be a potent kappa opioid receptor agonist, and three alkaloids (1-3) were shown to have micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the P. nitida alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid-preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which novel opioids with unique pharmacologic properties and therapeutic utility can be developed. DOI: 10.1021/acs.jnatprod.0c01036 PMCID: PMC7932029 PMID: 33326237 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing financial interest. 3. J Org Chem. 2020 Aug 21;85(16):10884-10890. doi: 10.1021/acs.joc.0c01448. Epub 2020 Aug 11. Hunzeylanines A-E, Five Bisindole Alkaloids Tethered with a Methylene Group from the Roots of Hunteria zeylanica. Zhang J(1), Yuan MF(1), Li ST(1), Sang CC(1), Chen MF(1), Ao YL(1), Li ZW(1), Xie J(1), Ye WC(1), Zhang XQ(1). Author information: (1)Institute of Traditional Chinese Medicine & Natural Products, and Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM & New Drugs Research, Jinan University, Guangzhou 510632, P. R. China. Five novel bisindole alkaloids, hunzeylanines A-E (1-5), with an unprecedented skeleton were isolated from the roots of Hunteria zeylanica. Compounds 1-5 represent the first examples of akuammine-pleioarpamine-type bisindole alkaloids fused with a dihydropyran unit. Their structures including absolute configurations were established through comprehensive spectroscopic data analyses and computational calculation methods. The plausible biogenetic pathway of 1 was also proposed. Alkaloids 1 and 2 displayed moderate cytotoxicity toward three human cancer cell lines (MDA-MB-231, AV3, and Huh7). DOI: 10.1021/acs.joc.0c01448 PMID: 32806090 [Indexed for MEDLINE] 4. J Am Chem Soc. 2018 May 23;140(20):6483-6492. doi: 10.1021/jacs.8b03404. Epub 2018 May 15. Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies. Picazo E(1), Morrill LA(1), Susick RB(1), Moreno J(1), Smith JM(1), Garg NK(1). Author information: (1)Department of Chemistry and Biochemistry , University of California , Los Angeles , California 90095 , United States. The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S)-cathafoline, (+)-akuammiline, and (-)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof. DOI: 10.1021/jacs.8b03404 PMCID: PMC6085837 PMID: 29694031 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing financial interest. 5. J Am Chem Soc. 2016 Feb 3;138(4):1162-5. doi: 10.1021/jacs.5b12880. Epub 2016 Jan 19. Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (-)-2(S)-Cathafoline, and (-)-Aspidophylline A. Moreno J(1), Picazo E(1), Morrill LA(1), Smith JM(1), Garg NK(1). Author information: (1)Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States. The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (-)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described. DOI: 10.1021/jacs.5b12880 PMCID: PMC5154302 PMID: 26783944 [Indexed for MEDLINE]