Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to the identification of the biphenylsulfonamides as a novel series of endothelin-A (ETA) selective antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found to be optimal at the 4'-position. Introduction of an amino group at the 2'-position also led to improved analogues. Combination of the optimal 4'-isobutyl substituent with the 2'-amino function afforded an analogue (20, BMS-187308) with improved ETA binding affinity and functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect caused by an ET-1 infusion in rats. Doses of 10 and 30 micromol/kg iv 20 attenuated the pressor responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.

Central vision loss disrupts voluntary shifts of spatial attention during visual search. Recently, we reported that a simulated scotoma impaired implicit spatial attention towards regions likely to contain search targets. In that task, search items were overlaid on natural scenes. Because natural scenes can induce explicit awareness of learned biases leading to voluntary shifts of attention, here we used a search display with a blank background less likely to induce awareness of target location probabilities. Participants searched both with and without a simulated central scotoma: a training phase contained targets more often in one screen quadrant and a testing phase contained targets equally often in all quadrants. In Experiment 1, training used no scotoma, while testing alternated between blocks of scotoma and no-scotoma search. Experiment 2 training included the scotoma and testing again alternated between scotoma and no-scotoma search. Response times and saccadic behaviors in both experiments showed attentional biases towards the high-probability target quadrant during scotoma and no-scotoma search. Whereas simulated central vision loss impairs implicitly learned spatial attention in the context of natural scenes, our results show that this may not arise from impairments to the basic mechanisms of attentional learning indexed by visual search tasks without scenes.