Robert W. Carling

Anticonvulsant activity of glycine-site NMDA antagonists. 2. trans 2-carboxy-4-substituted tetrahydroquinolines.

Abstract Anticonvulsant activity has been optimized in a series of glycine-site NMDA antagonists based on 2-carboxy tetrahydroquinoline, leading to the benzylamine 7 (L-690,590), its methyl ester prodrug 13 (L-691,470) and the phenylalanine 8 (L-696,833) which have ED 50 values of 39, 31.5 and 29 mg/kg (i.p.) respectively in the DBA/2 mouse audiogenic seizure model. Correlations between in vivo and in vitro activities suggest that systemic anticonvulsant action of glycine antagonists depends on both brain penetration as well as ‘access’ to receptors within the brain.

Studies on the synthesis of gloeosporone - synthesis of the proposed 2,8-disubstituted oxocane structure

Abstract Gloeosporone is neither the cis - nor the trans -2,8-disubstituted oxocane (1) nor its tautomer (2) whose total syntheses are described in this Letter.

4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors

The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.

Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists

Abstract 3-Substituted-2-quinoloners ( 6–8 ) have been identified as glycine-site N-methyl-D-aspartate receptor antagonists. It is proposed that the α-phenyl lactam unit in the potent 4-hydroxy-3-phenyl derivatives ( 7d and 8b , L-701,315) may act as a glycine bioisostere in receptor recognition.

Synthetic methodology for the preparation of trans- and cis-2,9-disubstituted oxonanes

Abstract Methylenation of the racemic lactone (5), followed by stereoselective hydroboration, gave predominantly the trans-2,9-disubstituted oxonane (7) which was converted into the carbon skeleton (1) of obtusenyne (2). Epimerisation of the trans-aldehyde (18) gave the cis-compound (19). Relative stereochemistry was established by the asymmetric synthesis of trans-(2R),(9R)-dimethyloxonane (13) and meso cis-2,9-dimethyloxonane (17).

Anticonvulsant activity of glycine-site NMDA antagonists. 1. 2-carboxyl prodrugs of 5,7-dichlorokynurenic acid

Anticonvulsant activity in the DBA/2 mouse audiogenic seizure model has been obtained in water-soluble prodrug esters of the glycine-site NMDA antagonist 5,7-dichlorokynurenic acid (1), leading to the 1-methyl(2-dimethylamino)ethyl ester 10 (ED50 62 mg/kg i.p.), which shows no behavioural stimulation at the anticonvulsant dose.

Synthesis of iminomethano-dibenzo[a,e]cyclooctenes by transannular formation and cleavage of isoxazolidines

Abstract Regioselective formation of the 7-azabicyclo[4,2,2]decanone (4) was accomplished by reaction of hydroxylamine with the enone (10) and subsequent reduction of the isoxazolidine adduct (11); intramolecular nitrone cycloaddition of (19) gave a 2:1 mixture of the regioisomers (17) and (18) which were reduced to give the bridgehead methylated, exo -hydroxylated, [3,3,2] and [4,2,2] iminomethano compounds (5) and (6).

A new synthesis of eight-membered lactones containing a 5,6-double bond

Claisen rearrangement of the vinyl ketene acetals (7; a, R = CH2OSiPh2 But, or b, R = n-pentyl) which are generated in situ by syn-elimination of the corresponding selenoxides (6a,b) in refluxing xylene gave the eight-membered lactones (8a,b).

A new synthetic method for the preparation of 2,8-disubstituted oxocane derivatives: synthesis of lauthisan and laurenan

The cis-disubstituted oxocanes lauthisan (1) and laurenan (2) have been prepared from the lactone precursors (9b) and (9a) respectively by a sequence in which the key steps were methylenation and stereoselective hydroboration of the resulting enol ethers (11b) and (11a).