S. Richard Baker

3,5-DIHYDROXYPHENYLGLYCINE IS A HIGHLY SELECTIVE AGONIST FOR PHOSPHOINOSITIDE-LINKED METABOTROPIC GLUTAMATE RECEPTORS IN THE RAT HIPPOCAMPUS

Abstract: Metabotropic glutamate receptors (mGluRs) are a heterogeneous family of G protein‐coupled glutamate receptors that are linked to multiple second messenger systems in the CNS. In this study the selectivity of mGluR agonists for different mGluR second messenger effects was characterized in slices of the rat hippocampus. The mGluR agonists (1S,3R)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid and (2S,3S,4S)α‐(carboxycyclopropyl)glycine produced multiple effects on second messengers that included enhanced phosphoinositide hydrolysis in both adult and neonatal rat hippocampus, inhibition of forskolin‐stimulated cyclic AMP (cAMP) formation in adult tissue, and increases in basal cAMP formation in the neonatal hippocampus. In contrast, 3,5‐dihydroxyphenylglycine was potent and effective in increasing phosphoinositide hydrolysis in both adult and neonatal hippocampus but unlike the other mGluR agonists did not inhibit forskolin‐stimulated cAMP formation (in the adult) or substantially enhance basal cAMP formation (in the neonate). Thus, in the rat hippocampus mGluR agonist‐mediated increases or decreases in cAMP formation are not secondary to mGluR‐mediated changes in phosphoinositide hydrolysis. Furthermore, 3,5‐dihydroxyphenylglycine can be used to activate subpopulations of mGluRs coupled to phosphoinositide hydrolysis with minimal effects on cAMP‐mGluR second messenger systems.

(+)-2-Methyl-4-carboxyphenylglycine (LY367385) selectively antagonises metabotropic glutamate mGluR1 receptors

Abstract The synthesis of three novel 4-carboxyphenylglycine derivatives is described. 2-Methyl substituents increase the antagonist potency compared to (S)-4CPG at mGluR1 receptors. Resolution of compound 1 showed that the activity resided in the (+)-isomer LY367385.

Evidence for multiple leukotriene D4 receptors in smooth muscle

Using pure leukotriene D4 (LTD4) as the agonist, we determined the dissociation constants, Kb and pA2 values, for the selective leukotriene antagonist FPL 55712 on guinea pig ileum, trachea, and parenchyma. Responses of the 3 tissues to LTD4 were competitively antagonized by FPL 55712. Kb and pA2 values were similar for trachea and parenchyma. However, these values differed from those obtained in ileum. We propose the existence of multiple LTD4 receptors, with those in lung differing from LTD4 receptors in ileum.

Identification and Pharmacological Profile of a New Class of Selective Nicotinic Acetylcholine Receptor Potentiators

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto)thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (α1β1γδ, α2β4, α3β2, α3β4, α4β2, α4β4, and α7) expressed in mammalian cells or Xenopus oocytes. At α2β4, α4β2, α4β4, and α7, but not α1β1γδ, α3β2, or α3β4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, GABAA, and N-methyl-d-aspartate receptors or voltage-gated Na+ and Ca2+ channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at α4β2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [3H]epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.

Enantiospecific synthesis of (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid by a modified Corey-Link reaction

Abstract ( 1S,2S,5R,6S )-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) was synthesised enantiospecifically from a sugar derived enantiomerically pure cyclopentenone. The α-amino acid stereogenic centre was formed by reacting the ketone with chloroform anion and then the alcohol so formed was reacted with sodium azide/DBU in methanol to give an azido ester. Critically, this modified Corey-Link reaction gives the opposite stereochemical outcome to the traditional Bucherer-Bergs and Strecker reactions. The azide was reduced and acylated, the 1,2 diol deoxygenated and the protecting groups removed to give LY354740 with an e.e.>98%.

Enzymatic resolution and pharmacological activity of the enantiomers of 3,5-dihydroxyphenylglycine, a metabotropic glutamate receptor agonist

Abstract 3,5-Dihydroxyphenylglycine (3,5-DHPG) was resolved using an aminoacylase enzyme in solution, and the enantiomers characterised for ability to stimulate metabotropic glutamate receptor (mGluR) mediated phosphoinositide hydrolysis in rat hippocampus. The mGluR activity resided mainly in the (S) enantiomer, which should thus be a useful tool to further explore mGluR pharmacology and function.

Synthesis of leukotriene A4 methyl ester from D-glucose

Abstract A high yielding synthesis of leukotriene A 4 methyl ester is described which uses D-glucose as starting material

Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1S,2S,5R,6S-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: Identification of a Potent, Selective Metabotropic Glutamate Receptor Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino Terminal Domain Structures.

As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

A radical approach to debenzylation of amides

Abstract The deprotection an N -benzylamides can be achieved under neutral conditions by reaction with N -bromosuccinimide in boiling chlorobenzene or ethyl acetate. Good to excellent yields are obtained using either acyclic or cyclic amides.

The comparative in vitro pharmacology of leukotriene D4 and its isomers

Abstract The 5R,6S and 5S,6R isomers of leukotriene D4 (LTD4), 9cis LTD4, 9cis,11trans LTD4 and 11trans LTD4 were synthesized for comparative pharmacological studies on intestinal and respiratory smooth muscle preparations. The 5S,6R isomers are biologically active, modification of the double bond stereochemistry causing only a moderate reduction in activity. The 5R,6S isomers possess approximately 1% the biological activity of their respective 5S,6R forms.