7 research outputs found
Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy
Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy
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Synthesis and Behavioral Evaluation of Novel Psychedelics as Potential Treatments for Pain and Mood Disorders
Serotonin 2A receptor (5-HT2aR) agonists and κ-opioid receptor (KOR) agonists have been demonstrated to be effective treatments for several central nervous system (CNS) disorders including depression, anxiety, addiction, and pain. In a recent clinical study, psilocybin (a classical hallucinogen) was shown to significantly decrease the symptoms of Major Depressive Disorder (MDD) and Treatment Resistance Depression (TRD) in humans for up to six weeks after a single dose. Several KOR agonists have been shown to be effective treatments of chronic pain without the physical dependence risks of µ-opioid receptor agonists. Also, due to KOR’s involvement in a biological anti-reward system, agonists for this receptor possess anti-addiction properties as demonstrated by their ability to decrease the self-administration of drugs of abuse in multiple different animal species.
Despite the great therapeutic potential for both these classes of molecules, their hallucinogenic and disassociate effects have been a major roadblock in the approval new pharmaceuticals.This dissertation describes the synthesis and behavioral evaluation of known and novel 5-HT2aR and KOR agonists. In the first half, the synthesis of several molecules related to the structure of ibogaine are described and the novel “oxa-iboga” class is introduced. One of the molecules in this class, oxa-noribogaine, has been evaluated in a variety of in vivo mouse tests including tail-flick, open field, and forced swim test. The results demonstrate that oxa-noribogaine is a potent KOR agonist and analgesic but has a lower side-effect profile compared to other KOR agonists such as noribogaine, epi-oxa-noribogaine, and U50,488H.
In the second half, two emerging classes of antidepressants, NMDAR antagonists and 5-HT2aR agonists, are described. Molecules from both these classes cause rapid acting antidepressant effects that can be induced after a single dose. This is a sharp contrast to traditional antidepressants such as SSRIs which require 4-6 weeks of consistent use before therapeutic effects are achieved. In our lab, a set of substituted phenethylamines which act as 5-HT2aR agonists were evaluated in vivo in the head twitch assay, forced swim test, sucrose preference test, and fear extinction assays. Their hallucinogenic and antidepressant-like effects are reported. One molecule, 4-CT, was designed and synthesized based on the structure of Ariadne, a 5-HT2aR agonist with low or no psychedelics effects. 4-CT produced a decreased number of head twitches compared to DOI (a hallucinogenic research control) and showed possible antidepressant-like effects in the forced swim test
Fluorinated Analogs of Organosulfur Compounds from Garlic (Allium sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies
We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested
Correction: Block et al. Fluorinated Analogs of Organosulfur Compounds from Garlic (<i>Allium sativum</i>): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies. <i>Molecules</i> 2017, <i>22</i>, 2081
In the original publication [...
Site Selective C-H Functionalization of Mitragyna Alkaloids Reveals a Molecular Switch for Tuning Opioid Receptor Signaling Efficacy
Mitragynine is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We developed a new synthetic method for selective functionalization of the unexplored C11 position of the mitragynine scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. We discovered that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. In the 7-hydroxymitragynine (7OH) series, the high efficacy parent compound was transformed to an equipotent low efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests after systemic administration. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.</p
Fluorinated Analogs of Organosulfur Compounds from Garlic (Allium sativum): Synthesis, Chemistry and Anti-Angiogenesis and Antithrombotic Studies
We describe the synthesis, reactivity, and antithrombotic and anti-angiogenesis activity of difluoroallicin (S-(2-fluoroallyl) 2-fluoroprop-2-ene-1-sulfinothioate) and S-2-fluoro-2-propenyl-l-cysteine, both easily prepared from commercially available 3-chloro-2-fluoroprop-1-ene, as well as the synthesis of 1,2-bis(2-fluoroallyl)disulfane, 5-fluoro-3-(1-fluorovinyl)-3,4-dihydro-1,2-dithiin, trifluoroajoene ((E,Z)-1-(2-fluoro-3-((2-fluoroallyl)sulfinyl)prop-1-en-1-yl)-2-(2-fluoroallyl)disulfane), and a bis(2-fluoroallyl)polysulfane mixture. All tested organosulfur compounds demonstrated effective inhibition of either FGF or VEG-mediated angiogenesis (anti-angiogenesis activity) in the chick chorioallantoic membrane (CAM) or the mouse Matrigel® models. No embryo mortality was observed. Difluoroallicin demonstrated greater inhibition (p < 0.01) versus organosulfur compounds tested. Difluoroallicin demonstrated dose-dependent inhibition of angiogenesis in the mouse Matrigel® model, with maximal inhibition at 0.01 mg/implant. Allicin and difluoroallicin showed an effective antiplatelet effect in suppressing platelet aggregation compared to other organosulfur compounds tested. In platelet/fibrin clotting (anti-coagulant activity), difluoroallicin showed concentration-dependent inhibition of clot strength compared to allicin and the other organosulfur compounds tested