| Abstract
| - Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDLcholesterol levels to a greater extent than other drugs. However, it has some side effects, amongwhich severe skin flushing is the most frequent and often limits patients' compliance. In asearch for novel agonists for the recently identified and cloned G protein-coupled nicotinic acidreceptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to havesubstantial affinity for this receptor. The affinities were measured by inhibition of [3H]nicotinicacid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinicacid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleenmembranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo[3,3,04,8]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) provedactive with Ki values of approximately 0.15 μM and EC50 values of approximately 6 μM, whiletheir intrinsic activity was only ∼50% when compared to nicotinic acid. Even slightly moreactive was 5-butylpyrazole-3-carboxylic acid (4g) with a Ki value of 0.072 μM, an EC50 value of4.12 μM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsicactivity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of Gprotein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibitedthe maximum effect elicited by 100 μM nicotinic acid and concentration dependently shiftednicotinic acid concentration−response curves to the right, pointing to a competive mechanismof action.
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