J. R. Smythies

Native fluorescence and hallucinogenic potency of some amphetamines

Die native Fluoreszenz einiger Methoxy-und Bromomethoxyamphetamine wurde bestimmt. Da die Fluoreszenz eines Moleküls zum Teil von der Energie seinerπ-Elektronen abhängig ist und die Stärke der halluzinogenen Aktivität dieser Verbindungen in einer positiven Beziehung zu ihrer HMP-Energie steht, wurde die Intensität der Fluoreszenz mit der Stärke der halluzinogenen Aktivität in Beziehung gebracht.

A mechanism for the interaction of a histone and DNA

Abstract 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).

Encephalitogenic protein: Aβ-pleated sheet conformation (102–120) yields a possible molecular form of a serotonin receptor

Es besteht die Annahme (Carnegie 1970), dass das basische Gehirnprotein als Rezeptor für Serotonin wirkt, und es wird der Vorschlag für molekularbiologische Reaktionen von Serotonin-Rezeptoren gemacht.

The behavioral effects of 2,5-dimethoxy-4-alkyl amphetamines

Le comportement des rats a été fortement influencé par des dérivés de la 2,5-diméthoxyamphétamine Le mécanisme possible de laction des hallucinogènes est discuté.

Molecular mechanisms of adrenergic receptors

Abstract Molecular models indicate that a simple complex of two pentapeptide segments of protein chain, plus one molecule of ATP and one of PGE, can construct a receptor for adrenaline that explains much of the SAR data on β-agonists and antagonists. A similar complex but without the PG can exert a cognate role for the α-receptor. The hypothesis is presented that this protein is part of adenylcyclase, for which PGE and adrenaline are coenzymes. The change of only two amino acids can convert this into a model for a site at which PGF rather than PGE can be effective. Alternatively the β-receptor can be constructed of a protein-PG complex, or solely of protein, in which case its action is allosteric. Some experiments to test the hypotheses are suggested.

The design of some new compounds to block psychotomimetic drugs

Abstract Predictions were made from theory; (i) that N,N-diethylactamide (DAA) would not, but (ii) that N,N-diethylbutyramide (DBA) would block dimethyltryptamine (DMT) and (iii) DBA would not block mescaline or 2,5-dimethoxy-4-methyl-amphetamine (DOM). Experiments using the Bovet-Gatti profiles in rats confirmed these predictions.

The effects of nicotinamide on mouse sleep

Après avoir reçu pendant 21 jours une injection quotidienne de 250 mg/kg nicotinamide, des souris ont été examinées chroniquement par lEEG. La nicotinamide prolonge la phase de sommeil et fait augmenter les mouvements oculaires.

On the molecular mechanism of interaction between the neurophysins and oxytocin and vasopressin

Abstract Detailed mechanisms are presented at the molecular level for the binding of oxytocin and of vasopressin to their carrier proteins neurophysin (NP) I and neurophysin II. The amino acid sequence of both these is known together with the pattern of disulphide bound formation for the latter. It is suggested that the peptide hormone fits snugly into a deep cavity in the protein carrier, so that the complex forms a globular, water-extruding mass. Features of the mode of interaction determined by experiment [such as the binding of the terminal amino group of the hormone to a carboxyl group of NP, the close binding of tyr and phe of the hormone to a lipophilic region of NP and the close relation of tyr (2) of the hormone with tyr (49) of NP]are built into the model. The differences between NPI and NPII are related to differences between oxytocin (ile at 3) and vasopressin (phe at 3). Finally a number of specific predictions are made that are testable by experiment concerning the X-ray structure of the NP-hormone complexes and the ease and result of chemical modification of specific residues.

Endogenous Hallucinogens in Cerebrospinal Fluid

The search for an endogenous psychotogen as a biochemical cause or biochemical indicator of schizophrenia was stimulated in 1952 when Harley-Mason, Osmond, and Smythies suggested that abnormal transmethylation of an endogenous amine could possibly produce a psychotomimetic compound.11 Much of the research activity in the years that followed focused on methylated metabolites of tryptamine, such as dimethyltryptamine (DMT) and O-methylbufotenin (OMB), as putative endogenous psychotogens. These compounds are strongly hallucinogenic, and biochemical evidence has been presented to show that precursors and enzymes required for their synthesis are found in mammalian brain in vivo.9,12 Many studies did, in fact, provide evidence for the presence of these compounds in urine and blood, but the significance of these findings with respect to the etiology of schizophrenia has been criticized on the grounds that the assays were not sufficiently specific or sensitive. More recent studies using sophisticated mass spectrometric analyses have confirmed earlier positive results on the presence of DMT in blood and urine and have provided more accurate quantification.10,15 However, direct correlations between the concentration of these hallucinogens in blood and psychiatric illness have not yet been described.