Willard Mckowan Welch

Atropisomeric quinazolin-4-one derivatives are potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists

Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.

Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist

The hypothesis that aberrant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity contributes to epileptogenesis and neurodegeneration has prompted the search for AMPA receptor antagonists as potential therapeutics to treat these conditions. We describe the functional characterization of a novel quinazolin-4-one AMPA receptor antagonist, 3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one (CP-465,022). This compound inhibits AMPA receptor-mediated currents in rat cortical neurons with an IC(50) of 25 nM. Inhibition is noncompetitive with agonist concentration and is not use- or voltage-dependent. CP-465,022 is selective for AMPA over kainate and N-methyl-D-aspartate receptors. However, the compound is found to be equipotent for AMPA receptors composed of different AMPA receptor subunit combinations. This is indicated by the finding that CP-465,022 is equivalently potent for inhibition of AMPA receptor-mediated responses in different types of neurons that express different AMPA receptor subunits. Thus, CP-465,022 provides a new tool to investigate the role of AMPA receptors in physiological and pathophysiological processes.

CP-465,022, a Selective Noncompetitive AMPA Receptor Antagonist, Blocks AMPA Receptors but Is Not Neuroprotective In Vivo

Background and Purpose— &agr;-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition. Methods— To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. Results— CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. Conclusions— Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-d-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.

Synthetic and mechanistic studies involving the condensation of penicillin grignards and boron trifluoride activated oxime ethers

Abstract High stereocontrol is observed in the BF3 mediated condensation of anions derived from mono and dibromopenicillanic ester sulfones and oxime ethers.

Discovery of a series of (4,5-dihydroimidazol-2-yl)-biphenylamine 5-HT7 agonists.

A novel (4,5-dihydroimidazol-2-yl)-biphenylamine series of 5-HT(7) agonist compounds was developed from a structurally related lead compound 1. The newly discovered series is exemplified by compound 2 that possesses high affinity for 5-HT(7) receptors and shows intrinsic agonist activity in functional assays. This new series has significant alpha(1) and alpha(2) activities perhaps due to the presence of the 2-aminoimidazoline moiety.

Methaqualone derivatives are potent noncompetitive AMPA receptor antagonists

Quinazolin-4-one derivatives of methaqualone substituted at C-2 define a new class of noncompetitive antagonists at AMPA receptors.

Chapter 1. Antipsychotic and Antianxiety Agents

Publisher Summary This chapter examines the development of antipsychotic and antianxiety agents. Clozapine has emerged as the focus of clinical and theoretical interest in the antipsychotic area based on its extremely low incidence of extrapyramidal side reactions. Structure–activity relationships (SAR) of the tricyclic psychotherapeutics and clinical experience with the long-acting neuroleptics have been reviewed. The SAR studies in the dibenzo[b,f]thiepin and related 6,7,6 systems have shown that substitution by chlorine in the 9-position of perathiepin results in diminished activity. Important pharmacokinetic study correlated chlorpromazine (CPZ) plasma levels with therapeutic response and found that plasma levels in the range of 150–300 ng/ml usually corresponded to clinical improvement. Concomitant administration of an antiparkinson agent (trihexyphenidyl) tended to lower plasma levels of CPZ, an effect ascribed to reduce gastric motility and decreased absorption of CPZ. A series of benzodiazepine (2, halazepam) showed evidence of efficacy against acute psychotic symptoms in an uncontrolled tria1. CI-686 was predicted to have major tranquilizer activity of short duration on the basis of quantitative pharmaco-EEG studies. Butaclamol possessed pharmacological actions resembling fluphenazine, with activity residing solely in the (+)-enantiomer.