Peter M. Burden

The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine.

Many abused substances have been found to possess anxiogenic-like or/and anxiolytic-like properties. Discrepancies about the effects of MDMA, one of the most popular recreational drugs in recent years, on anxiety have been seen in the literature, and almost all of the data in this respect were derived from retrospective studies. The present study was thus designed to examine the drugs actions by using an animal model of anxiety, the elevated plus-maze test in male mice. Intraperitoneal MDMA at 1 mg/kg was ineffective, at 4 mg/kg decreased the percent of open arm entries (p < 0.01), and increased enclosed entries (p < 0.05), at 12 mg/kg had no significant effect, and at 20 mg/kg induced an increase of percent of open time (p < 0.01). As control drugs, amphetamine (0.5-4 mg/kg, i.p.) produced a dose-dependent, anxiogenic-like effect and diazepam (1 mg/kg, i.p.) induced an anxiolytic-like effect in the test. The results indicate that MDMA has anxiogenic-like properties at lower doses and anxiolytic-like at higher doses. The effects of MDMA and amphetamine on the mouses responses to the plus-maze are compared. These findings provide a possible explanation for the controversies over MDMAs effects on anxiety in the literature.

Neuropharmacology: Propylene Glycol Elicits Anxiolytic-like Responses to the Elevated Plus-maze in Male Mice

Propylene glycol is a common solvent often contained in injectable solutions of anxiolytics of low water‐solubility, such as diazepam (Valium) and pentobarbital (Nembutal). Several studies have shown that propylene glycol can have an inhibitory effect on the central nervous system. This study, using ethanol for comparison, further examined whether propylene glycol has anti‐anxiety properties.

Novel Cyclic Phosphinic Acids as GABAC ρ Receptor Antagonists: Design, Synthesis, and Pharmacology

Understanding the role of GABAC receptors in the central nervous system is limited due to a lack of specific ligands. Novel γ-aminobutyric acid (GABA) analogues based on 3-(aminomethyl)-1-oxo-1-hydroxy-phospholane 17 and 3-(guanido)-1-oxo-1-hydroxy-phospholane 19 were investigated to obtain selective GABAC receptor antagonists. A compound of high potency (19, K B = 10 μM) and selectivity (greater than 100 times at ρ1 GABAC receptors as compared to α1β2γ2L GABAA and GABAB(1b,2) receptors) was obtained. The cyclic phosphinic acids (17 and 19) are novel lead agents for developing into more potent and selective GABAC receptor antagonists with increased lipophilicity for future in vivo studies.

An improved, versatile synthesis of the GABAC antagonists (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and (piperidin-4-yl)methylphosphinic acid (P4MPA)

A simple, versatile and economical synthesis of the highly selective GABAC antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) and the saturated analogue P4MPA is described. TPMPA is prepared in high yield in five steps via a palladium catalysed C–P bond forming reaction.

Diastereoselective synthesis of (±)-(3-aminocyclopentane)alkylphosphinic acids, conformationally restricted analogues of GABA

A divergent synthesis of both diastereoisomers of (+/-)-(3-aminocyclopentane)alkylphosphinic acid is described. Both diastereoisomers are obtained in 5 steps from the key (+/-)-(3-hydroxycyclopent-1-ene)alkylphosphinate esters which are prepared via a palladium catalysed C-P bond forming reaction.

The synthesis of 1,8-disubstituted 10,11-dihydrodibenz[b,f]oxepin-10-ones. analogues of anaesthetic steroids

1,8-Disubstituted 10,11-dihydrodibenz[b,f]oxepin-10-ones 4a, b and 5a, b have been synthesised as analogues of steroid anaesthetics 2 and 3 respectively. The novel partial Ullmann reaction between methyl 2,6-dichlorophenylacetate 7 and 4-substituted phenols 8e, b gave diphenyl ether derivatives 9a, b. The latter were then hydrolysed and cyclodehydrated to give 1,8-disubstituted 10,11-dihydrodibenz[b,f] oxepin-10-ones 11a, b which underwent selective functional group transformations to give 4a, 5a and 4b, 5b respectively. Lithium borohydride reduction of the ester 13b to the benzyl alcohol 14b proceeded without reduction of the enol ether function.

Ring-C aromatic steroids. Part 5. C-17 Hydroxylation and side-chain degradation of 18-nor-17α(H)- and -17β(H)-pregna-4,8,11,13-tetraene-3,20-dione. X-Ray structure of 17β-hydroxy-18-nor-17β(H)-pregna-4,8,11,13-tetraene-3,20-dione

The procedure for 17-hydroxylation of pregnan-20-ones using oxygen, butoxide, and triethyl phosphite was extended to steroid analogues with aromatic C-rings, viz. 18-nor-17α(H)- and -17β(H)-pregna-4,8,11,13-tetraene-3,20-dione (and to 1-acetylindan). At temperatures higher than that we adopted (–50 °C), side-chain cleavage to give the 17-ketone (or equivalent) became prominent. Results of an X-ray crystallographic study on one of the two 17-epimeric C-aromatic products, 17β-hydroxy-18-nor-17β(H)-pregna-4,8,11,13-tetraene-3,20-dione, are presented. The crystals are orthorhombic, space group P212121, with four molecules in a cell of dimensions a= 9.643(3), b= 17.043(4), c= 10.015(3)A. The structure was solved by direct methods and refined by full-matrix least-squares calculations; R= 0.059 for 1 219 observed reflections. Ring A has a 1α,2β-half -chair conformation, ring B is in a 5α,6β-half-chair conformation, aromatic ring C is planar, and ring D is a C(16)β-envelope. Molecules are linked to form infinite chains by intermolecular O–H ⋯ O hydrogen bonds [O ⋯ O 2.801 (4)A].

The synthesis of 2-cyclohexylideneperhydro-4,7-methanoindenes. Non-steroidal analogues of steroidal GABAA receptor modulators

Racemic (3aα,4β,7β,7aα)-2-cyclohexylideneperhydro-4,7-methanoindene derivatives (±)-3 and (±)-4 were synthesised as analogues of steroidal GABAA receptor modulators 1 and 2 respectively. The lithium dianion generated from epimeric 2,3,3a,4,7,7a-hexahydro-4,7-methano-1H-indene-2-carboxylic acids, 8 and 9, reacted with a commercially available cyclohexanone to generate β-hydroxy carboxylic acids. Cyclodehydration to β-lactones followed by the thermal elimination of carbon dioxide gave a suitably functionalised 2-cyclohexylidenehexahydro-4,7-methano-1H-indene derivative 18. Regio- and stereospecific hydrocyanation of the bicyclo[2.2.1]hept-2-ene moiety of 18 was achieved via hydroboration affording a racemic nitrile, 19. This underwent further transformations to give (±)-3 and (±)-4 and their hydroxy group epimers (±)-5 and (±)-6 respectively. X-Ray structure data was obtained for (±)-3. The effects of compounds (±)-3–(±)-6 on the binding of the GABAA receptor agonist [3H]muscimol to rat synaptic membranes were measured. Compound (±)-4 was a weak positive modulator while the others were inactive.

A Facile Synthesis of 2-Imino-1-pyrrolidinealkanoic Acids

Abstract Sulfuryl chloride isocyanate was used in a mild, one pot conversion of methyl 2-oxo-1-pyrrolidinealkanoic acid esters 5–7 to their corresponding 2-imino-1-pyrrolidinealkanoic acids 2–4.

Ring-C aromatic steroids. Part 4. The C-aromatic analogue of progesterone

The ring-C aromatic analogue of progesterone, 18-norpregna-4,8,11,13-tetraene-3,20-dione (2), was formed together with its 17-epimer (3) when 9α,11α-epoxy-20ξ-hydroxy-3-oxopregn-4-eno-18,20-lactone (14) was subjected to oxidative decarboxylation, and the resulting products treated with boron trifluoride. The precursor (14) was synthesised as follows. 11α-Hydroxyprogesterone (4) was dehydrated, and the product then selectively reduced (by two routes) to 20β-hydroxypregna-4,9(11)-dien-3-one (9). The latter was functionalised at C-18 to give 3-oxopregna-4,9(11)-dieno-18,20-lactone (10) which was oxidised, after opening of the lactone ring, to the corresponding lactol (12). The latter was converted into the required lactol epoxide (14). Internal displacement on the 9α,11α-epoxide occurred when the lactol epoxide (14) was treated with acid, yielding 9α-hydroxy-3,20-dioxopregn-4-eno-18,11β-lactone (16).