The slowly activating delayed rectifier K+ current, IKs, is an important modulator of cardiac action potential repolarization. Here, we describe a novel benzodiazepine, [L-364,373 \[(3- R )-1,3-dihydro-5-(2-fluorophenyl)-3-(1 H -indol-3-ylmethyl)-1-methyl-2 H -1,4-benzodiazepin-2-one\] (R-L3), that activates IKs and shortens action potentials in guinea pig cardiac myocytes. These effects were additive to isoproterenol, indicating that channel activation by R-L3 was independent of β-adrenergic receptor stimulation. The increase of IKs by R-L3 was stereospecific; the S -enantiomer, S-L3, blocked IKs at all concentrations examined. The increase in IKs by R-L3 was greatest at voltages near the threshold for normal channel activation, caused by a shift in the voltage dependence of IKsactivation. R-L3 slowed the rate of IKs deactivation and shifted the half-point of the isochronal (7.5 sec) activation curve for IKs by −16 mV at 0.1 μm and −24 mV at 1 μm. R-L3 had similar effects on cloned KvLQT1 channels expressed in Xenopus laevis oocytes but did not affect channels formed by coassembly of KvLQT1 and hminK subunits. These findings indicate that the association of minK with KvLQT1 interferes with the binding of R-L3 or prevents its action once bound to KvLQT1 subunits.

A Novel Benzodiazepine that Activates Cardiac Slow Delayed Rectifier K+ Currents

Nonpeptidic ligands for peptide-activated G protein-coupled receptors.

Small molecule ligands for oxytocin and vasopressin receptors.

Structural simplification: an efficient strategy in lead optimization.

The succinimide ring is incorporated into hundreds of compounds that are widely used as agricultural, industrial, and pharmaceutical agents. Some succinimide derivatives that contain an aryl group on the ethylene bridge of the succinimide ring (C-arylsuccinimides) or on the nitrogen atom (N-arylsuccinimides) induce nephrotoxicity in humans and/or laboratory animals. Acute toxicity induced by this general class of compounds is typically characterized as polyuric renal failure, while chronic nephrotoxicity is seen as chronic interstitial nephritis. In this review, the structure–nephrotoxicity relationships, biotransformation, and mechanisms of nephrotoxicity for the C- and N-arylsuccinimides are examined.

Nephrotoxicity induced by c- and n-arylsuccinimides

Non-peptide oxytocin antagonists: identification and synthesis of a potent camphor aminosuccinimide

Coupling of the benzophenones (I) with D-tryptophan methyl ester hydrochloride (II) gives the benzodiazepinones (III).

Design of Nonpeptidal Ligands for a Peptide Receptor: Cholecystokinin Antagonists.

The structure activity relationships of a series of non-peptide oxytocin antagonists containing a camphor aminosuccinimide as a key structural element were investigated. A potent and selective analog was identified and prepared in diastereomerically pure form starting from aspartic acid.

N. P. Gould

Papers

Non-peptide oxytocin antagonists: identification and synthesis of a potent camphor aminosuccinimide

Design of Nonpeptidal Ligands for a Peptide Receptor: Cholecystokinin Antagonists.

Non-Peptide Oxytocin Antagonists: Identification and Synthesis of a Potent Camphor Aminosuccinimide.