Pauline J. Sanfilippo

Potential anxiolytic agents. 3. Novel A-ring modified pyrido[1,2-a]benzimidazoles

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Potential Anxiolytic Agents. Part 4: Novel Orally-Active N5-Substituted Pyrido[1,2-a]benzimidazoles with High GABA-A Receptor Affinity

A series of pyrido[1,2-a]benzimidazoles (PBIs) with substitution on the N(5)-nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24, which has an IC(50) of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.

Syntheses and biological evaluation of two new naproxen analogs

Abstract Reported herein are the syntheses and biological activities of two structural analogues ( 2 and 3 ) of naproxen ( 1 ).

Analytical and preparative high-performance liquid chromatographic separation of thienopyran enantiomers

Abstract The analytical and preparative enantiomeric resolution of a racemic substituted thienopyran was obtained with a β-cyclodextrin bonded-phase column using isocratic conditions. Baseline separations were obtained with short run times. The analytical method is accurate, reliable and reproducible for measuring enantiomeric excess. A semi-preparative high-performance liquid chromatographic method was used to obtain the enantiomers for pharmacological testing prior to developing an asymmetric synthesis of RWJ 26629.

Section Review Central & Peripheral Nervous Systems: Novel anxiolytic agents - 1994 to present

The treatment of anxiety disorders remains an active area of research. Behavioural tests developed in the 1960s have been augmented by specific receptor binding assays. Selective modulation of these binding sites offers the hope that the abuse liability, sedation and ethanol interaction found with earlier drugs can be removed entirely or in part. Although most anxiolytic drug discovery continues to be centred on the neurotransmitters γ-aminobutyric acid (GABA) and serotonin (5-HT), research in other areas such as those involving cholecystokinin (CCK), corticotrophin releasing factor (CRF) and neuropeptide Y (NPY) also has promise for the future. This article reviews the primary and patent literature in the anxiolytic area for 1994 to the present.

Thiopene systems. 15. Synthesis and antihypertensive activity of 7- (subsituted benzamido)-6-hydroxythieno[3,2,-b]pyrans as nwe potassium channel activitors

The synthesis and antihypertensive activity of novel 7-(subsituted benzamido)-6-hydroxy-5,5- dimethylthieno[3,2-b]pyrans are described. Acetyl substitution on the thiophene significantly increases potency of these benzamides in contrast to the nitro substitution which gives the best results in the 7-(cyclic amido)-6- hydroxythieno[3,2-b]pyran series. Compound 21 is 3-fold more potent than the benzopyran cromakalim(2).

Novel thieno[2,3-b]- and [3,4-b]pyrans as potassium channel openers. Thiophene systems--XVII.

The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (+/- 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (+/- 1).