Publications by authors named "James Bicksler"
As part of an effort to identify 5-HT(1A) antagonists that did not possess typical arylalkylamine or keto/amido-alkyl aryl piperazine scaffolds, prototype compound 10a was identified from earlier work in a combined 5-HT(1A) antagonist/SSRI program. This quinolyl-piperazinyl piperidine analogue displayed potent, selective 5-HT(1A) antagonism but suffered from poor oxidative metabolic stability, resulting in low exposure following oral administration. SAR studies, driven primarily by in vitro liver microsomal stability assessment, identified compound 10b, which displayed improved oral bioavailability and lower intrinsic clearance.
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- Kv1.1 channels are found in various brain and spinal cord regions and contribute to neuron hyperpolarization when expressed alone, but co-expression with Kvbeta1 switches them to a fast inactivating current, increasing neuron excitability.
- A yeast two-hybrid screen was used to find compounds that prevent Kv1.1 inactivation by Kvbeta1, identified as 'disinactivators,' which also showed potential in reducing seizure activity in mice.
- These disinactivators work through various mechanisms, likely interacting with the Kvbeta1 N-terminus or its binding site on Kv1.1, offering a possible treatment strategy for conditions like epilepsy and neuropathic pain.