3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. A Combined NMR and CoMFA Approach

Abstract

The present work focuses on the study of the three-dimensional (3D) structural requirements for selective antagonist activity of arylpyrazole compounds at the cannabinoid CB1 and CB2 receptors. Initially, a combined high-resolution two-dimensional (2D) NMR and computer modeling approach was carried out to study the solution structure of the key pyrazole derivative N-(piperidin-1-yl)-5-phenyl-1-(n-pentyl)-4-methyl-1H-pyrazole-3-carboxamide (AM263). By using the NMR-determined molecular conformers as templates, the 3D quantitative structure-activity relationship (QSAR) studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of arylpyrazole cannabinoid receptor antagonists. Molecular alignments suitable for deriving valuable pharmacophoric features for this series of compounds were determined. Such systematic 3D-QSAR/CoMFA analyses of 29 molecules and their receptor affinities gave guidance for understanding the binding affinities of arylpyrazoles at the CB1 and CB2 binding sites, respectively. Comparison of CoMFA steric and potential contour maps for affinity at the two cannabinoid receptor subtypes helps to differentiate structural requirements for each subtype and serves as a basis for the design of later-generation analogues.

Recent CB1 cannabinoid receptor antagonists and inverse agonists

“…The neutral antagonist analog A6a was tested in newborn mice, establishing neutral antagonism of CB1 as a component in failure-to-thrive syndrome [Fride et al, 2007]. AM263 (A7a; X5 H; Ki 5 11.1 nM), an N1 n-pentyl substituted analog of rimonabant, was examined in a three-dimensional quantitative structureactivity relationship (QSAR) study that combined nuclear magnetic resonance and comparative molecular field analysis methods [Chen et al, 2006]. The results identified (1) a requirement of a bulky substituent at N1, (2) enhanced binding due to steric and electrostatic interactions from a negatively charged bulky substituent (i.e., halogen) on the diaryl pyrazoles at the para-position of the C-5 aryl ring, (3) a disfavored CB1 binding affinity due to steric bulk at the distal region of the N-amido substituent, (4) a methyl on the pyrazole C-4 favoring high CB1 affinity and selectivity versus CB2, and (5) negatively charged groups proximal to the carbonyl oxygen favoring CB1 binding as factors for further ligand design.…”

Modelling Atypical Small‐Molecule Mimics of an Important Stem Cell Cytokine, Thrombopoietin

“…0.6. [58] While cross-validated q 2 values are typically used to evaluate the validity of the QSAR models, few 3D QSAR models reported employ independent test sets as a measure of model performance. As Golbraikh and Tropsha [54] and Kubinyi et al [59] have shown, cross-validated q 2 values and test set r 2 values do not always correlate significantly.…”

Regioselective synthesis of diazaspiro[4.4]nona‐ and tetrazaspiro[4.5]deca‐2,9‐diene‐6‐one derivatives

“…Thus, attachment of other heterocyclic moieties, which are known to possess pharmacological activity, to furan ring may lead to the fulfillment of this objective. On the other hand, pyrazole derivative are known to have significant biological and pharmacological activity [7][8][9]. As an extension of our research program aiming at the synthesis of a variety of heterocyclic systems for biological screening [10][11][12][13][14][15][16][17][18][19][20], we report here on the syntheses of some important diazospiro [4.4]nona-and tetrazaspiro [4.5]deca-2,9-diene-6-one derivatives.…”