Roger Graham Hall

CGP 35348 : a centrally active blocker of GABAB receptors

The biochemical, electrophysiological and pharmacological properties of the new GABAB receptor blocker CGP 35348 are described. In a variety of receptor binding assays CGP 35348 showed affinity for the GABAB receptor only. CGP 35348 had an IC50 of 34 microM at the GABAB receptor. The compound antagonized (100, 300, 1000 microM) the potentiating effect of L-baclofen on noradrenaline-induced stimulation of adenylate cyclase in rat cortex slices. In electrophysiological studies CGP 35348 (10, 100 microM) antagonized the effect of L-baclofen in the isolated rat spinal cord. In the hippocampal slice preparation CGP 35348 (10, 30, 100 microM) blocked the membrane hyperpolarization induced by D/L-baclofen (10 microM) and the late inhibitory postsynaptic potential. CGP 35348 appeared to be 10-30 times more potent than the GABAB receptor blocker phaclofen. Ionophoretic and behavioural experiments showed that GABAB receptors in the brain were blocked after i.p. administration of CGP 35348. This compound may be of considerable value in elucidating the roles of brain GABAB receptors.

The Importance of Fluorine in the Life Science Industry

Fluorine-containing compounds are at the leading edge of many new developments in the life science industry. In recent years a steady increase in the number of fluorinated organic molecules reaching commercial status as crop protection products and pharmaceutical drugs has been observed: in 1978, ca. 600 pesticides were known, but only approximately 25 (4%) contained fluorine. Today, fluorine-containing compounds account for more than 17% of all commercially available crop protection agents and many others are currently under development. The structures of the fluorine-containing development compounds proposed for ISO common names between 1997 and 2002 are highlighted in this paper. In the pharmaceutical area around 220 fluorinated drugs were on the market in 1990, representing ca. 8% of all synthetic drugs. Six years later already more than 1500 fluorine-containing drugs were under development. Fluorine-containing compounds have also been successful in the marketplace, such as the insecticides fipronil and lambda-cyhalothrin, the fungicides epoxiconazole and trifloxystrobin, the herbicides trifluralin and clodinafop, and the pharmaceutical blockbusters Fluoxetine (Prozac®), Paroxetine (Paxil®), Ciprofloxacin (Cipro®) and Cisaprid (Propulsid®). This success is mainly due to the fact that selectively fluorinated compounds can exhibit dramatically improved potency when compared to the non-fluorinated analogues. The incorporation of fluorine into a biologically active compound alters the electronic, lipophilic and steric parameters and can critically increase the intrinsic activity, the chemical and metabolic stability, and the bioavailability. The positive effects of fluorine on the biological efficiency is outlined by three examples: in the chemical class of herbicidal thiatriazines, the presence or the absence of fluorine leads to dramatic effects on the biological activity; the metabolic stability and the pharmacokinetics of aminopyrazinone acetamide thrombin inhibitors were improved by the introduction of fluorine, and in a novel class of insecticides/acaricides any modification of the gem-difluorovinyl group results in a strong decrease of biological activity.

Total synthesis of (±)-rocaglamide and some aryl analogues

Abstract The insecticidal activity found for rocaglamide and its congeners, prompted us to establish a short and efficient synthesis of the natural product and some synthetic ‘halo-aryl’ analogues. Pd-catalysed cross-coupling reactions of the bromo analogue were then explored in order to gain a suitable access to a broad range of unnatural analogues. The key step of our approach is a keto-aldehyde acyloin ring-closure followed by a Stiles carboxylation.

GABAA and GABAB receptors in locus coeruleus: effects of blockers

Racemic baclofen, (-)-baclofen and muscimol depressed all spontaneously firing locus coeruleus neurons tested in a slice preparation. Racemic phaclofen (100 microM; 1 mM) moderately antagonized the effects of racemic baclofen without antagonizing those of muscimol. Bicuculline (10, 30, 100 microM) potently antagonized the action of muscimol without affecting the inhibition of baclofen. Phaclofen and bicuculline had no pronounced effect on the spontaneous discharge rate of cells. The results suggests that there are GABAA and GABAB receptors in the locus coeruleus.

3-aminopropanephosphinic acid is a potent agonist at peripheral and central presynaptic GABAB receptors

The actions of the GABA analog 3-aminopropanephosphinic acid (3-APA) were studied in the guinea-pig isolated ileal preparation and at synapses between cultured rat hippocampal neurons. Like the GABAB receptor agonist, baclofen, 3-APA inhibited the electrically evoked ileal twitch. The EC50 for 3-APA was 0.8 microM; the EC50 for baclofen was 9 microM. In addition, the depressant responses to 3-APA and baclofen were blocked by the GABAB receptor antagonists phaclofen, saclofen, 2-hydroxy-saclofen and delta-aminovaleric acid. 3-APA also mimicked the presynaptic action of baclofen at GABAergic synapses between embryonic rat hippocampal neurons in culture. 3-APA reduced the amplitude of inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) by greater than 50% at a concentration of 1 microM, while baclofen reduced synaptic transmission to a similar degree at 10 microM. 3-APA did not alter membrane conductance, nor did the drug alter postsynaptic responses to GABA. These data show that 3-APA is a potent agonist at presynaptic GABAB receptors in the periphery and on GABAergic neurons from the central nervous system. The activity of 3-APA at central postsynaptic GABAB receptors remains to be studied.

Differing actions of baclofen and 3-amino-propylphosphinic acid in rat neocortical slices

Rat neocortical slices maintained in Mg2(+)-free Krebs medium developed spontaneous paroxysmal discharges which were attenuated or suppressed by the gamma-aminobutyric acid-B (GABAB) receptor agonist baclofen, occasionally accompanied by a slight hyperpolarisation, and antagonised by the specific GABAB-receptor antagonist, 2-OH-saclofen. Over the same dose range, the GABA-analogue 3-amino-propylphosphinic acid (3-APA) caused a marked, prompt hyperpolarisation with little or no effect on the frequency of the discharges, although their amplitude was attenuated. In the presence of 2-OH-saclofen, 3-APA still induced a hyperpolarisation but the amplitude of the discharges was no longer affected. This marked difference in action between baclofen and 3-APA in the rat neocortical slices suggests there may be a heterogeneity of GABAB-receptors.

Synthesis and structure-activity relationships of benzophenone hydrazone derivatives with insecticidal activity.

A broad range of benzophenone hydrazone derivatives was prepared and tested against selected chewing insect pests, allowing the analysis of structure-activity relationships. Good activity was found only when the aromatic rings were substituted at the 4-positions with an halogen atom and a triflate or perhaloalkoxy group. In contrast, a number of substituents on the hydrazone part led to active compounds, the best results being achieved with acyl-type substituents. The excellent laboratory and greenhouse activity of the best representatives was confirmed in semi-field trials against Spodoptera littoralis.

Synthesis of the carbocyclic analogue of (±)-Rocaglamide

Abstract The carbocyclic analogue of (±)-Rocaglamide 1 , in which the ring oxygen of the 2,3-dihydrobenzofuran has been replaced by a methylene group, was synthesised in 10 steps from cyclopentanone. A key feature of this route is a highly efficient intramolecular condensation reaction which cleanly leads to the tricyclic skeleton.

New syntheses of arylphosphinic acids from the reaction of ethyl diethoxymethylphosphinate with aryl bromides and phenols

The chemistry of the hypophosphorous acid synthon, ethyl diethoxymethylphosphinate 1 has been further developed to afford efficient new routes to arylphosphinic acids 6 and 2-hydroxyphenylphosphinic acids 10. In one approach, a palladium(0) catalysed P–H insertion has been used; the second approach utilises a lithium-based ortho rearrangement of aryl phosphonates, readily prepared from the Atherton–Todd reaction of 1 with phenols. In both cases, the phosphinic acids were obtained in a final step by acid deprotection.

Synthesis and insecticidal activity of 4-perhaloalkoxy (or thioalkyl) benzophenonehydrazone derivatives†

Benzophenonehydrazone derivatives containing a mesylate or triflate substituent are known to exhibit insecticidal activity. In the present study, such substituents have been replaced by perhaloalkoxy groups. High levels of activity against lepidopteran pests were observed in greenhouse trials. For optimum activity, the substituents should be relatively small. In semi-field trials, however, none of the compounds tested showed sufficient persistence to warrant further development.