Alexander Senning

Piracetam and other structurally related nootropics

Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.

Studies of dithiiranes and thiosulfines as reactive intermediates

Abstract Indirect, but compelling evidence for the intermediacy of dithiiranes 1 and thiosulfines 2 has been found by us and is also provided by literature data. The intriguing dithiirane → dithioester rearrangement as well as most of the interrelations and conversions postulated in Scheme 1 have been demonstrated experimentally. In a number of cases acetyl α-chloroalkyl disulfides 16 (X = Cl, Y = COCH3) are useful starting materials for the synthesis of thioamides such as 40.

Studies on amino acids and peptides. XII: Synthesis of thiated analogues of Boc-S-Ala-Aib-S-Ala-OMe and Ac-S-Ala-Aib-S-Ala-OMe

The two model peptides Boc-S-Ala-Aib-S-Ala-OMe (1a) and Ac-S-Ala-Aib-S-Ala-OMe (1b) and their monothiated analogues Boc-S(R)-AlaΨ(CSNH)-Aib-S-Ala-OMe (3a), Boc-S-Ala-AibΨ(CSNH)-S-Ala-OMe (4a), AcΨ(CSNH)-S-Ala-Aib-S-Ala-OMe (2b), Ac-S-Ala-AibΨ(CSNH)-S-Ala-OMe (4b),and the dithiated Boc-S-AlaΨ(CSNH)-AibΨ(CSNH)-S-Ala-OMe (5a) are synthesized. Peptide 3a was obtained from the coupling of HCl·H-S-Ala-OMe to 5-2-(1-(tert-butoxycarbonyl-amino) ethyl-4,4-dimethyl-1,3-thiazol-5(4H)-one (11). The thioamide analogues 4a (together with 5a) and 2b were obtained by regioselective thiation of the respective model peptides 1a and 1b using 2,4-bis(4-methylphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide, Lawessons Reagent (LR). Deprotection of the Boc group of 4a followed by acetylation of the product, afforded 4b. The magnetic nonequivalence of the gem-methyl groups of Aib is discussed.

Studies of electron-depleted thiocarbonyl compounds—IV : Reactions of trithiocarbonate S,S-dioxides with 1,3-dienes and with tetramethylallene☆

Abstract The trithioorthocarboxylate S,S-dioxides B, a new class of compounds, can be conveniently prepared from trithiocarbonate S,S-dioxides 1 either by Diels-Alder reaction with suitable 1,3-dienes or by ene reaction with tetramethylallene. The monocyclic Diels-Alder adducts 4 readily lose sulfinic acid to yield the 2H-thiopyrans 5, while treatment of 4 with catalytic amounts of acid results in rearrangement to the isomeric Δ2-dihydrothiopyrans 6.

Molecular and crystal structures of two β-bend forming monothiated analogues of melanostatin

Abstract The molecular and crystal structures of two monothiated analogues of melanostatin, namely t-Boc-L-Proψ(CSNH)-L-Leu-Gly-NH2 (1)C and L--Top-L-Leu-Gly-NHEt (2), determined by X-ray diffraction analyses, are reported. In compound (1) the tertiary urethane bond adopts the cis conformation. Both tripeptide amides are folded in a type-II β-bend conformation at the -L-Leu-Gly-sequence. A weak intramolecular H bond, involving the thioamide sulfur atom as the acceptor, is a significant characteristic of compound 1. The two structures are discussed, in particular, in comparison to those of H-L-Pro-L-Leu-Gly-NH2, and t-Boc-L-Pro-L-Leu-Gly-NH2, the latter recently solve in the Padova laboratory.

Synthesis, structure, and reactions of thiocarbonic acid derivatives new pentathiodipercarbonates, (RSS)2 CS, α,α,α-tris(disulfides), and the first α,α,α-tris(trisulfide)

Abstract Novel bis(perhaloalkyl) pentathiodipercarbonates 5b-d have been synthesized by reaction of sulfenyl chlorides with metal trithiocarbonates, and the heptathio analog 21a was prepared similarly. Lenthionine 19 is the main product when diiodomethane is treated with sodium tetrathiopercarbonate. A rearrangement of bis(alkyldithio)chloromethanesulfenyl chlorides 22 to alkyldithio) (alkyltrithio)dichloromethanes 24 has been observed. Additions of sulfenyl chlorides and of thiosulfenyl chlorides to the thiocarbonyl compounds 5 and 21a were achieved in acetonitrile. The structures of the first crystalline pentathiodipercarbonate 5a and α,α,α-tris(disulfide) 29a , and of the first reported α,α,α-tris(trisulfide) 31a have been determined by X-ray crystallography.

Secondary acrylamides in nyloprint® printing plate as a source of contact dermatitis

Several chemically pure fractions have been isolated from Nyloprint® printing plates. 5 of the fractions elicited positive patch test reactions in 7 Nylonprint® allergic printers. 4 of the 5 components were analysed by means of nuclear magnetic resonance, infrared spectrophotometry, mass spectrometry and elemental analysis. The fractions were identified as N,N′‐methylene‐bis‐acrylamide, N,N′‐[oxybis(methylene)]bis‐2‐propenamide, N,N′‐[1,2‐ethanediylbis(oxymethylene)]‐2‐propenamide, and a new compound N‐[(2‐hydroxyethoxy‐methyl]‐2‐propenamide. All of the analysed fractions have the common feature of being secondary acrylamides.

Different sensitising acrylic monomers in Napp® printing plate

3 chemically pure fractions were isolated from Napp® printing plate and subsequently identified by means of nuclear magnetic resonance, infrared spectrophotometry and elemental analysis. 1 of the fractions elicited positive test reactions in 3 Napp®‐allergic printers, and another fraction also elicited a positive test reaction in 1 of the printers. The 2 allergens were 2‐hydroxyethyl methacrylate and N.N′‐methylene‐bis‐acrylamide. The 1st of the 2 allergens was also demonstrated in another printing plate, Nyloprint WD®.

α,β-Unsaturated Isothiocyanates

Abstract The synthesis and the properties of α,β-unsaturated isothiocyanates are described with 276 literature references.

The Preparation of Stable α-Chlorosulfenyl Chlorides from Sterically Crowded Tetramethylcyclobutanethiones and Chlorine

The sterically crowded 2,2,4,4-tetramethyl-3-thioxocyclobutanone (7) and its dithio analogue 9 were found to react readily with gaseous chlorine to afford 1:1 and 1:2 adducts, respectively. The stable, crystalline products were identified as the α-chlorosulfenyl chlorides 8 and 12 which yielded corresponding disulfides after treatment with equimolar amounts of thioacetic acid.