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9-Diazomethylanthracene reacts with carboxyl groups to give an ester derivative which can be used as either a fluorescence or ultraviolet label for fatty acid analysis by high-pressure liquid chromatography. The limit of detection by ultraviolet spectroscopy was demonstrated to be approximately 150 pg/μl of the individual fatty acid esters. Fluorescence detection showed a limit of approximately 15 pg/μl. The fluorescence detector response was linear from 0.49 to 14.2 pmol/μl. Thus, derivatization of fatty acids with 9-diazomethylanthracene provides a new and very sensitive method for the quantification of picomole quantities of fatty acids by high-pressure liquid chromatographic techniques using either ultraviolet or fluorescence detection.

The serotonin (5-HT) receptor affinities and behavioral (discriminative stimulus) properties of a series of 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropanes (2,5-DMA) were investigated. The substituents at the 4-position included H, OMe, OEt, Me, Et, F, Br, I, and NO2. Substituent lipophilicities (pi values) of these functionalities appear to have a minimal effect on either 5-HT receptor affinity or behavioral activity. Those derivatives previously found to be most potent in human studies possess significant affinity for 5-HT receptors. Furthermore, when rats trained to discriminate (+/-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline were used, generalization was found to occur upon administration of the 4-substituted 2,5-DMA derivatives. Because a direct relationship exists between the ED50 values obtained from these discrimination studies and human hallucinogenic potencies, the discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

The incidence and quantities of dimethyltryptamine and O-methyl-bufotenine were studied in the cerebrospinal fluid of patients suffering acute schizophrenic illnesses and in surgical and neurological control groups. Some schizophrenic patients have higher levels of both amines than do controls, though the differences in distribution did not reach statistical significance in the sample studied. The gas-chromatographic technique used is sensitive at the low picogram level.

A procedure for the separation, characterization and detection of picogram quantities of biogenic indolealkylamines contained in cerebrospinal fluid (CSF) has been described. It involves extracting these amines from CSF, converting them to their respective O- and/or N-perfluoroacyl derivatives with N-heptafluorobutyrylimidazole, and finally subjecting the mixture of derivatives to gas-liquid chromatographic separation. The unknown amines may be identified by direct comparison with known standards. Quantification can be achieved through comparison of the indolealkylamine peak areas with standard curves prepared from pure derivatized standards.

A mechanism is suggested at the molecular level whereby histone IIB 2 can act as a cross-link between two (or possibly three) adjacent and parallel strands of DNA double helix some 40 A apart. Application of Prothero's rule and the Lewis probability functions indicate the probable locations of three a -helices and a number of β-turns. This, coupled with the requirement that the tertiary conformation of the histone be complementary to the DNA molecules and for as many basic groups as possible to bind to phosphate oxygens, allows us to suggest, on the basis of model building using accurate space-filling (CPK) models, a complex conformation that achieves this. A similar process applied to histone IIB 1 , whose complete amino acid sequence is also known, shows the location of five probable a -helices, a number of β-turns, and a segment of β-pleated sheet. The basic amino acids are gathered in four groupings. Model building experiments suggest that histone IIB 1 forms a complex strut joining four parallel strands of DNA double helix that form a diamond with diameters 100 and 40 A. In both these models the purpose and function of a fair proportion of the individual amino acids can be specified. This paper is the third and last of a series in this Journal in which models are presented for the tertiary conformation and function of all five histones of known (in whole or in part) amino acid sequence. This suggests that all five are concerned in packing the long DNA double helix, which may be in a “square helix” form, into the confined space of the chromosome. The hypotheses may be tested by a direct investigation of nucleoprotein in situ to see if these 40, 70, and 100 A interhelical distances can be detected by biophysical methods.

The amino acid sequence of histone F2A1 has been determined and physical evidence indicates the molecule has a high proportion of α-helical conformation. If the hypothesis is made that the sequence 33–98 forms an α-helix a possible binding site for a 16 base segment of DNA in an extended conformation is apparent. The histone molecule bears a spiral ridge rich in positively charged groups running beside a spiral groove with a mainly lipophilic floor. This can accommodate the phosphate groups (bound to the charged groups on the ridge) and ribose and base hydrocarbons (in the groove). The segment 1–31 of the histone in a β conformation can now run down alongside the DNA molecule in the same groove and forms multiple complementary bonds with selected amino acids on the α-helical portion (on one side) and with the DNA molecule (on the other side). A tentatively suggested base sequence of the DNA to achieve an optimal “fit” is CTTCCPCCCC??PCCT. The purpose of this relationship may be to allow the DNA molecule to make an acute bend or possibly the histone may act as a represser. (P = purine base).

Two behavioural indices for psychotomimetic activity have been used to elucidate the probable role of methoxy group configuration in the mescaline molecule. The first method using a shuttle box CAR has been reported previously in this series. The second is based on the Sidman Avoidance schedule and utilizes the Bovet-Gatti profiles. Our results indicate that only two analogues of mescaline are active-the 2,3,4,5 and 2,3,4,5,6 compounds. This indicates that the 3,4,5 configuration is necessary and that adding extra methoxy groups increases activity. The great activity of the penta methoxy compound may be due to the fact that this compound substituted in the 2 and 6 positions cannot be metabolized by mescaline oxidase. The significance of these results is discussed.

An hypothesis has been presented earlier based on binding experiments that the ACh storage and release mechanism in the cholinergic terminal is based on a stack of CMP molecules. Such a stack can bind ACh in a 1 : 1 ratio and the resulting ACh-CMP complex is stereochemically complementary to morphine (1 : 1 : 1) and related drugs. The amino acid sequence of scorpion neurotoxin II (Androctonus australis Hector) has recently been published. This paper presents a model of the conformation of this protein, including its pattern of disulphide bond formation, that is to a high degree complementary to a stack of nine molecules of CMP. The conformation of the protein is predicted at two levels of confidence: (1) high (amino acids 48–64) and (2) tentative (amino acids 1–47). If this theoretical conformation is confirmed by direct biophysical studies this will provide evidence in favour of the CMP hypothesis.

Aus den substituierten Benzaldehyden (I) und Nitroathan (II) entstehen die Nitropropene (III), die mit Eisen/HCI zu den Phenylacetonen (IV) reduziert werden.

Synthesis of 7-(N,N′-trimethyl)-5-methoxytryptamine from 2,5-dimethylpyrone via 4-methoxy-2,6-dimelhylnitrobenzene and 5-melhoxy-7-methylindole is described.

IT has been suggested1–3 that the ionic permeability of membranes is controlled by complex formation on the surface between various phosphorylated nucleosides and protein chains. This is based on the fact that guanine, cytidine and adenine are complementary to glutamate, arginine, and glutamine respectively and all four bases are complementary to glutamine. Adenosine triphosphate (ATP) has been reported to bind strongly to rat brain synaptosomal protein—probably to glutamine moieties4. It is postulated that complex formation is promoted by prostaglandins and disrupted by transmitters and on this basis it has been possible to suggest working molecular specifications for acetylcholine (ACh), γ-aminobutyric acid (GABA) and glutamate receptors based on guanine–glutamate and cytidine–arginine pairs, and for prostaglandin and catecholamine action based largely on the adenine–glutamine pairs. This hypothesis has explained a quantity of structure-activity relationship data on agonists and antagonists of these compounds as detailed in refs. 1–3.

The serotonin (5-HT) receptor affinities and behavioral (discriminative stimulus) properties of a series of 4-substituted derivatives of 1-(2,5-dimethoxyphenyl)-2-aminopropanes (2,5-DMA) were investigated. The substituents at the 4-position included H, OMe, OEt, Me, Et, F, Br, I, and NO2. Substituent lipophilicities (pi values) of these functionalities appear to have a minimal effect on either 5-HT receptor affinity or behavioral activity. Those derivatives previously found to be most potent in human studies possess significant affinity for 5-HT receptors. Furthermore, when rats trained to discriminate (+/-)-1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from saline were used, generalization was found to occur upon administration of the 4-substituted 2,5-DMA derivatives. Because a direct relationship exists between the ED50 values obtained from these discrimination studies and human hallucinogenic potencies, the discriminative stimulus paradigm, with DOM as a training drug, appears to be a useful tool for comparing the quantitative and qualitative (DOM-like) effects produced by certain hallucinogenic agents.

A series of N,N-dialkyltryptamines with methylthio or methylenedioxy substituents in the 4, 5, and 6 positions and methyl or isopropyl on the side-chain nitrogen has been synthesized. The behavioral pharmacology of these compounds showed them to possess Bovet-Gatti profiles characteristic of hallucinogens, and the 5-methylthio congener was the most potent. Binding studies at [3H]LSD and [3H]5-HT sites demonstrated that no single structural feature correlated with binding or behavioral changes and suggest a complex mode of action for these potential hallucinogenic agents.

(1) A general theory of the molecular structure of receptors published previously is adapted to the problem of prostaglandin (PG) receptors. (2) On a basis of the molecular structure of PGs a tentative ‘model receptor’ in protein is specified. (3) We have discovered that other biologically active agents are also complementary to this molecular structure. (4) Possible naturally occurring PG agonists comprise the so-called violent cathartics (e.g. rhein, ricinoleic acid, emodin, chrysophanic acid, colocynthin, gambogic acid and others) and the co-carcinogens anthralin and phorbol myristate acetate. (5) Possible naturally occurring PG antagonists comprise the anti-tumor agents maytansine, acromycine, datiscoside, hellebriginin 3-acetate, hymenoflorin and mycophenolic acid. (6) Experiments to test the hypothesis are suggested.

Contractions of sheep umbilical vasculature induced by 5-hydroxytryptamine, mescaline and d-lysergic acid diethylamide (LSD) were antagonized by 1-methyl-1, 2, 5, 6-tetrahydropyridine-N, N-diethyl-carboxamide (THPC) 5 X 10(-4)M. THPC did not block contractile responses to angiotensin. The data are interpreted to support our previous suggestions that certain chemical entities representing portions of the LSD molecule may be effectively studied as antagonists to the hallucinogens. The present data indicate that THPC is a weak 5-hydroxytryptamine receptor antagonist.

Serotonin receptor affinity and photelectron spectral data were obtained on a number of substituted N,N-dimethyltryptamines. Evidence is presented that electron-donating substituents in the 5-position lead to enhanced behavioral disruption activity and serotonin receptor affinity as compared to unsubstituted N,N-dimethyltryptamine and analogues substituted in the 4- or 6-position. Some correlation was found between ionization potentials and behavioral activity, which may have implications concerning the mechanism of receptor binding.

A series of N,N-dialkyltryptamines with methylthio or methylenedioxy substituents in the 4, 5, and 6 positions and methyl or isopropyl on the side-chain nitrogen has been synthesized. The behavioral pharmacology of these compounds showed them to possess Bovet-Gatti profiles characteristic of hallucinogens, and the 5-methylthio congener was the most potent. Binding studies at [3H]LSD and [3H]5-HT sites demonstrated that no single structural feature correlated with binding or behavioral changes and suggest a complex mode of action for these potential hallucinogenic agents.

2,4-Diamino-6-(bis-2-chloroethyl)aminomethyl pteridine has been synthesized and found to be highly potent against L-1210 mouse leukemia lymphoblasts. A single dose of 5 mg/kg injected 24 h after the tumor inoculation increased the life-span of 50% of mice to more than 200%, while the other 50% of animals were cured.

A general theory of the molecular structure of receptors for transmitters based only on protein has been presented elsewhere (Smythies, 1974a,b). The acetylcholine receptor at the neuromuscular junction is postulated in particular to be based on a Kusnetsov-Ghokov grid with four sequencestwo “primary” chains A-x-B-cys-A-x-B where A = arg or lys and B = glu or phosphoser and two “secondary” chains of sequence -gly-x-gly-pro-x-ile-cys-asp-x- forming a symmetrical receptor cup of rectangular form. The present paper extends the model to include the gate over the adjacent ionophore (or “ion conductance modulator”: ICM) and the linking mechanism from receptor to gate. These are postulated to consist of a second Kusnetsov-Ghokov grid generated by a third “primary” chain along the side that covers the orifice to the ion conducting channel. The action of ACh is postulated to be to displace an hydrated Ca++ ion from the receptor cup and to disrupt the AB rungs in the receptor grid. The middle primary chain then slides 14 A and the AB links reform. This replaces a bulky amino acid pair normally blocking the ion channel by a less bulky amino acid pair and so hydrated ions can be transmitted. It is further postulated that snake neurotoxins (ACh blockers) in a specified conformation bind mainly to the ionophore grid and prevent the sliding filament mechanism from opening; whereas the snake “cardiotoxins” (ACh agonists)—in a specified conformation—bind to the same sliding filament mechanism in its “open” ionophore gate and prevent it being closed: and histrionicotoxin binds to the same open “gate” but blocks it physically. The hypothesis may rigorously be tested by experiment as it makes detailed predictions on the X-ray structure of the snake neurotoxins and cardiotoxins.

The R(-) and S(+)-isomers of 2,5-dimethoxy-4-methylamphetamine (DOM) produce a dose-dependent hypothermia in rats kept in the cold (6 degrees C). 2 This hypothermia was linearly dependent upon ambient temperature and the R(-)-isomer was considerably more potent than the S(+)-isomer. 3 A statistically significant tachyphylaxis was observed when R(-)-DOM was administered on two successive days. The response seven days after the second injection was similar to that on the first day of injection. 4 The hypothermia induced by R(-) and S(+)-DOM was antagonized by methysergide but not by p-chlorophenylalanine (PCPA) or pimozide. Methysergide, PCPA or pimozide alone did not elicit hypothermia at the doses used. The results indicate that R(-) and S(+)-DOM act at post-synaptic 5-hydroxytryptamine receptors.

Le comportement des rats a ete fortement influence par des derives de la 2,5-dimethoxyamphetamine Le mecanisme possible de l'action des hallucinogenes est discute.