title: Pyrazole derivatives as partial agonists for the nicotinic acid receptor.
abstract: 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.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van Herk
authors.forename: J
authors.initials: J
authors.lastname: Brussee
authors.forename: A M C H
authors.initials: AM
authors.lastname: van den Nieuwendijk
authors.forename: P A M
authors.initials: PA
authors.lastname: van der Klein
authors.forename: A P
authors.initials: AP
authors.lastname: IJzerman
authors.forename: C
authors.initials: C
authors.lastname: Stannek
authors.forename: A
authors.initials: A
authors.lastname: Burmeister
authors.forename: A
authors.initials: A
authors.lastname: Lorenzen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000819:agonists; D066298:In Vitro Techniques; D009525:Niacin / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013154:Spleen / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011720:Pyrazoles; D011978:Receptors, Nicotinic; D009525:Niacin; D019204:GTP-Binding Proteins