Synthetic Studies Toward (+)-Lysergic Acid - Construction Of The Tetracyclic Ergoline Skeleton
Written by PoelieIntroduction:
Ergot alkaloids are biosynthesized by coupling of a variety of amine moieties with a common carboxylic acid, lysergic acid. Lysergic acid has attracted a lot of a attention because of it's unique tetracyclic structure as well as the interesting biological activities of ergot alkaloids. While numerous synthetic studies and total syntheses of racemic lysergic acid have been reported to date, the first total synthesis of (+)-lysergic acid was reported in 2004 by Szántay and coworkers, which involves tetracyclic intermediate using (–)-dibenzoyl-L-tartaric acid. We have recently achieved the total synthesis of (+)-lysergic acid methyl ester, featuring an enzymatic desymmetrization of a 1,3-diol, an addition of 2,6-dibromophenyllithium to a nitroalkene, and most notably a palladium-mediated double cyclization. While we were successful in the asymmetric synthesis of (+)-lysergic acid methyl ester, we are not particularly satisfied with the long synthetic route consisting of more than 30 steps. Herein, we report our more recent studies toward the total synthesis of (+)-lysergic acid.
HETEROCYCLES, Vol. 79, 2009
Tohru Inoue, Satoshi Yokoshima, and Tohru Fukuyama
Comparative potencies of MDMA analogues as inhibitors of [3H]noradrenaline and [3H]5-HT transport in mammalian cell lines
Written by PoelieBackground and purpose:
Illegal ‘ecstasy’ tablets frequently contain 3,4-methylenedioxymethamphetamine (MDMA)-like compounds of unknown pharmacological activity. Since monoamine transporters are one of the primary targets of MDMA action in the brain, a number of MDMA analogues have been tested for their ability to inhibit [3H]noradrenaline uptake into rat PC12 cells expressing the noradrenaline transporter (NET) and [3H]5-HT uptake into HEK293 cells stably transfected with the 5-HT transporter (SERT).
Experimental approach:
Concentration–response curves for the following compounds at both NET and SERT were determined under saturating substrate conditions: 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxy-N-hydroxyamphetamine (MDOH), 2,5-dimethoxy-4-bromophenylethylamine (2CB), 3,4-dimethoxymethamphetamine (DMMA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), 3,4-methylenedioxyphenyl-N-methyl-2-butanamine (MBDB) and 2,3-methylenedioxymethamphetamine (2,3-MDMA).
Key results:
2,3-MDMA was significantly less potent than MDMA at SERT, but equipotent with MDMA at NET. 2CB and BDB were both significantly less potent than MDMA at NET, but equipotent with MDMA at SERT. MBDB, DMMA, MDOH and the MDMA metabolites HMA and HMMA, were all significantly less potent than MDMA at both NET and SERT.
Conclusions and implications:
This study provides an important insight into the structural requirements of MDMA analogue affinity at both NET and SERT. It is anticipated that these results will facilitate understanding of the likely pharmacological actions of structural analogues of MDMA.
British Journal of Pharmacology (2007) 152, 1121–1130
T Montgomery, C Buon, S Eibauer, PJ Guiry, AK Keenan and GJ McBean
‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines
Written by PoelieAbstract
Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT2A receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system.
The present paper reports the synthesis and pharmacological evaluation of a series of ‘hybrid’ benzofuranyl–benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT2A agonist binding site. Thus, 4(a–b), 5(a–b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b0]difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT2A receptor. The behavioral pharmacology of these new analogs was also evaluated in the two-lever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a–b) displayed a 4- to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a–b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).
Bioorganic & Medicinal Chemistry 16 (2008) 6242–6251
Danielle M. Schultz, Jennifer A. Prescher, Stephanie Kidd, Danuta Marona-Lewicka, David E. Nichols and Aaron Monte,
Abstract
We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.
Lees het volledige artikel op PLoS one.
Ayahuasca–From Dangerous Drug to National Heritage: An Interview with Antonio A. Arantes1
Written by Joost BreeksemaHieronder een interview met professor Arantes over de wens van verschillende Braziliaanse ayahuasca groeperingen om erkend te worden als immateriaal cultureel erfgoed. Lees de samenvatting in het Engels hieronder. Bij de bronvermelding is het hele artikel te lezen en te downloaden.
Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later
Written by Joost BreeksemaHieronder volgen de samenvatting en het hele artikel van de follow-up study van het onderzoek uit 2006, die Griffiths et. al na 14 maanden hebben uitgevoerd, betreffende de psychologische effecten van een hoge dosis psilocybine in gezonde subjecten.
