ABSTRACT
The norditerpenoid alkaloid lycaconitine (2) was synthesized from lycoctonine (3) and its affinity determined for two neuronal nicotinic acetylcholine receptor subtypes. The structure of 2 was confirmed by a combination of spectroscopic methods.
Subject(s)
Alkaloids/pharmacology , Neurons/metabolism , Receptors, Nicotinic/metabolism , Alkaloids/chemical synthesis , Alkaloids/chemistry , Animals , Binding, Competitive/drug effects , Brain Chemistry/drug effects , In Vitro Techniques , Magnetic Resonance Spectroscopy , Membranes/drug effects , Membranes/metabolism , Neurons/drug effects , Rats , Receptors, Nicotinic/drug effects , Spectrophotometry, InfraredABSTRACT
Duclauxin, an antitumor agent, was isolated from sporulating Penicillium herquei (ATCC34665) grown on a medium of peanut hulls supplemented with potato starch solution (termed "Gostar"). The medium was inoculated with a sporulating subculture of P. herquei established on a 2% potato starch slurry supplemented with mineral salts. The P. herquei grew as well on Gostar as on an enriched medium. Duclauxin was isolated in crystalline form from Gostar-grown P. herquei. Comparison of costs of duclauxin obtained from inexpensive Gostar versus costly enriched media indicated that Gostar reduces production expenses. Duclauxin was not effective as an antibiotic against certain species of gram-positive and gram-negative bacteria, fungi, and viruses, but a concentration-dependent inhibition of wheat coleoptile growth was observed. Duclauxin was characterized by melting point, optical rotation, IR and NMR spectroscopy, MS and X-ray diffraction.
Subject(s)
Antibiotics, Antineoplastic/biosynthesis , Antibiotics, Antineoplastic/isolation & purification , Penicillium/growth & development , Penicillium/metabolism , Antibiotics, Antineoplastic/economics , Chemical Phenomena , Chemistry, Physical , Chromones/economics , Chromones/isolation & purification , Chromones/metabolism , Culture Media , Drug Resistance, Microbial , Magnetic Resonance Spectroscopy , Mass Spectrometry , X-Ray DiffractionABSTRACT
Extraction of the fungus Cladosporium cladosporioides yielded the known isocoumarin, cladosporin [1], and a new compound. This metabolite, which inhibited the growth of etiolated wheat coleoptiles slightly more than did cladosporin, was characterized as a diastereoisomer of cladosporin at C-14 and was named isocladosporin [2].
Subject(s)
Cladosporium/chemistry , Coumarins/chemistry , Mycotoxins/chemistry , Mycotoxins/pharmacology , Triticum/growth & development , Cladosporium/metabolism , Coumarins/isolation & purification , Coumarins/pharmacology , Isocoumarins , Mass Spectrometry , Molecular Conformation , Spectrophotometry, Ultraviolet , Stereoisomerism , Triticum/drug effectsABSTRACT
The fungal metabolites, citrinin (4,6-dihydro-8-hydroxy-3,4,5-trimethyl-6- oxo-3H-2-benzopyran-7-carboxylic acid) and DHMI (3,4-dihydro-6-methoxy-3,7-dimethyl-1H-2-benzopyran-8-ol), as well as certain synthetic derivatives, have been evaluated for aldose reductase inhibitory activity using a rat lens enzyme preparation. Citrinin and its reduction product, dihydrocitrinin, were found to have significant activity (IC50 approximately 10 microM), whereas the other compounds were 3-10 times less potent. Kinetic studies showed that citrinin was not an irreversible inhibitor of the enzyme, as might be expected of a quinone methide. Spectroscopic (NMR) evidence is presented for the existence of citrinin predominantly in the form of its hemi-acetal in aqueous solutions, suggesting that it is this benzo[c]pyran derivative which interacts with the enzyme, rather than the quinone methide form.
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Benzopyrans/pharmacology , Citrinin/analogs & derivatives , Citrinin/pharmacology , Animals , Eye/enzymology , Fungi/metabolism , Kinetics , Penicillium/chemistry , Rats , Structure-Activity RelationshipABSTRACT
cis-10-Hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b -octahydrobenzo[f]quinoline (4) is a centrally acting serotonin (5-HT) receptor agonist of moderate potency. Due to its semirigid character and the obvious similarity between (4aR,10bS)-4 and more potent, centrally acting 5-HT receptor agonist cis-(1S,2R)-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (2), we carried out the preparation (via resolution of 6, a precursor of 4) and the pharmacological testing of the enantiomers of 4. We were able to show that the active enantiomers of 4 and 2 coincide in terms of stereochemistry, i.e., that it is the 4aR,10bS enantiomer of 4 that is the more active one. The absolute configuration was assigned on the basis of single-crystal X-ray analysis of the precursor (+)-6 of the active enantiomer (-)-4. Conformational analysis with molecular mechanics (MM2) calculations were performed on the N-methyl analogues of compounds cis-(1S,2R)-2 (cis-(1S,2R)-3) and cis-(4aR,10bS)-4 (cis-(4aR,10bS)-7). Both ammonium and free amine forms were subjected to these calculations. The results show a preference for the N-equatorial conformation, which is corroborated by the X-ray structure of (+)-6.HCl. The relatively low potency of compound cis-(4aR,10bS)-4 might be explained by unfavorable direction of the N-lone pair (or ammonium hydrogen) bond in this compound as compared to cis-(1S,2R)-2 and trans-(4aR,10bR)-5, which can be predicted to be the more active enantiomer of compound 5.
Subject(s)
Hydroxyquinolines/pharmacology , Serotonin/metabolism , Animals , Chemical Phenomena , Chemistry, Physical , Male , Models, Molecular , Rats , Rats, Inbred Strains , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
A novel series of N,N-dimethylisotryptamine (isoDMT) derivatives, i.e., derivatives of 1-[2-(dimethylamino)ethyl]indole, was prepared and found to be isosteric with their corresponding N,N-dimethyltryptamine (DMT) counterparts with respect to serotonin receptor (rat fundus) affinity. Whereas the isoDMT derivatives possessed a greater affinity than did their corresponding DMT derivatives, they were relatively ineffective in displacing [3H]-5-HT binding from rat brain (cortex) homogenates. In a drug discrimination paradigm, using rats as subjects, 6-OMe-isoDMT produced effects similar to those of 5-OMe-DMT. Attempts to antagonize the discriminative stimulus effects of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) using two of the isoDMT derivatives proved unsuccessful.
Subject(s)
N,N-Dimethyltryptamine/chemical synthesis , Serotonin Antagonists/chemical synthesis , Tryptamines/chemical synthesis , Animals , Biological Assay , Brain/metabolism , Cell Membrane/metabolism , Discrimination Learning/drug effects , Indicators and Reagents , N,N-Dimethyltryptamine/analogs & derivatives , N,N-Dimethyltryptamine/pharmacology , Rats , Receptors, Serotonin/drug effects , Receptors, Serotonin/metabolism , Structure-Activity RelationshipSubject(s)
Discrimination Learning/drug effects , Serotonin/analogs & derivatives , DOM 2,5-Dimethoxy-4-Methylamphetamine/pharmacology , Animals , Conditioning, Operant/drug effects , Generalization, Stimulus/drug effects , Male , Rats , Rats, Inbred Strains , Serotonin/pharmacology , StereoisomerismABSTRACT
Animals (rats), trained to discriminate the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant procedure, were challenged with various doses of several indolealkylamine and phenalkylamine derivatives. In both series, the alpha-methyl analogs were found to be more active than either their N-methyl or alpha-demethyl counterparts. Furthermore, when the activities of the optical isomers of DOM were compared with the activities of S-(+) and R-(-)-alpha-methyltryptamine (alpha-MeT), it was found that the more potent isomer of alpha-MeT (i.e. S) possessed the opposite absolute configuration of the more potent isomer of DOM (i.e. R). With respect to the mechanism of action of these agents, these findings are not inconsistent with a common site hypothesis.
Subject(s)
Amphetamines/pharmacology , Behavior, Animal/drug effects , DOM 2,5-Dimethoxy-4-Methylamphetamine/pharmacology , Tryptamines/pharmacology , DOM 2,5-Dimethoxy-4-Methylamphetamine/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Hallucinogens/pharmacology , Male , N,N-Dimethyltryptamine/pharmacology , Rats , Rats, Inbred Strains , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Stimulus generalization studies were conducted using rats trained to discriminate 1.0 mg/kg of the phenalkylamine hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline in a two-lever operant procedure. The results suggest that certain indolealkylamine hallucinogens, including LSD and several alpha-methyltryptamine, N,N-dialkyltryptamine and beta-carboline derivatives, are capable of producing stimulus effects similar to those produced by DOM. Furthermore, for twelve agents where human data are available, a significant correlation exists between discrimination-derived ED50 values and hallucinogenic potency.
Subject(s)
Amphetamines/pharmacology , DOM 2,5-Dimethoxy-4-Methylamphetamine/pharmacology , Generalization, Stimulus/drug effects , Hallucinogens/pharmacology , Lysergic Acid Diethylamide/pharmacology , Animals , Carbolines/pharmacology , Male , N,N-Dimethyltryptamine/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Several dihydro and carbocyclic analogues of tryptamine were evaluated in order to determine the role of the heterocyclic portion of the indole nucleus on the interaction of indolealkylamines with the serotonin receptors of the rat fundus. Reduction of the C2--C3 double bond or replacement of the indole nitrogen with an sp3-hybridized carbon atom results in a 50% decrease in receptor affinity. Complete removal of the five-membered ring of N,N-dimethyltryptamine reduces affinity by an order of magnitude. It appears that an intact indole nucleus, though not entirely necessary, results in an optimal receptor interaction for the indolealkylamines examined.
Subject(s)
Tryptamines/metabolism , Animals , Male , Rats , Rats, Inbred Strains , Receptors, Serotonin/metabolism , Structure-Activity RelationshipABSTRACT
Several 7-substituted derivatives of N,N-dimethyltryptamine (DMT) were prepared and evaluated in the rat fundus serotonin receptor assay and in a behavioral (discriminative stimulus) assay in rats. Both 7-Me- and 5-OMe-7-Me-DMT possess a higher pA2, and 5,7-(OMe)2-DMT a lower pA2, than that of DMT itself. Like DMT, all three of these compounds produce behavioral effects in rats which are similar to those of the hallucinogen 5-OMe-DMT. Although 7-ET- and 7-Br-DMT possess a higher serotonin receptor affinity than DMT, neither produce behavioral effects which parallel those of 5-OMe-DMT. In contrast, 6-Me-DMT and its 5-OMe derivative do not interact with the serotonin receptors in a competitive manner and are inactive in the discriminative stimulus assay.
Subject(s)
N,N-Dimethyltryptamine/chemical synthesis , Tryptamines/chemical synthesis , Animals , Chemical Phenomena , Chemistry , In Vitro Techniques , Male , N,N-Dimethyltryptamine/analogs & derivatives , Prejudice/drug effects , Rats , Receptors, Serotonin/drug effectsABSTRACT
Examination of D. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.