Pyrazole derivatives as partial agonists for the nicotinic acid receptor
| Autor: | P. A. M. van der Klein, J. Brussee, T. van Herk, A. M. C. H. van den Nieuwendijk, Adriaan P. IJzerman, Christina Stannek, Anna Lorenzen, and A. Burmeister |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
G protein
Carboxylic acid Nicotinic Antagonists Pyrazole In Vitro Techniques Receptors Nicotinic Partial agonist Niacin chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship GTP-Binding Proteins Drug Discovery Adipocytes Animals Nicotinic Agonists Receptor chemistry.chemical_classification Cholesterol Cell Membrane Rats Nicotinic agonist chemistry Biochemistry Molecular Medicine Pyrazoles Alpha-4 beta-2 nicotinic receptor Spleen |
| Zdroj: | Journal of medicinal chemistry. 46(18) |
| ISSN: | 0022-2623 |
| Popis: | Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [(3)H]nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [(35)S]GTPgammaS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo[3,3,0(4,8)]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with K(i) values of approximately 0.15 microM and EC(50) values of approximately 6 microM, while their intrinsic activity was only approximately 50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a K(i) value of 0.072 microM, an EC(50) value of 4.12 microM, 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 intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 microM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competitive mechanism of action. |
| Databáze: | OpenAIRE |
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