A Theoretical Study of the Relationships between Electronic Structure and CB1 and CB2 Cannabinoid Receptor Binding Affinity in a Group of 1-Aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides

We report the results of a search for model-based relationships between hCB1 and hCB2 receptor binding affinity and molecular structure for a group of 1-aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides. The wave functions and local atomic reactivity indices were obtained at the B3LYP/6-31G(d,p) levels of theory with full geometry optimization. Interaction pharmacophores were generated for both receptors. The main conclusions of this work are as follows. (1) We obtained statistically significant equations relating the variation of hCB1 and hCB2 receptor binding affinities with the variation of definite sets of local atomic reactivity indices. (2) The interaction of the molecules with the hCB1 and hCB2 receptors seems to be highly complex and mainly orbital controlled. (3) The interaction mechanisms seem to be different for each type of receptor. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

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Regioselective synthesis and cannabinoid receptor binding affinity of N-alkylated 4,5-diaryl-1,2,3-triazoles

Medicinal Chemistry Research ◽

10.1007/s00044-012-9991-3 ◽

2012 ◽

Vol 21 (12) ◽

pp. 4473-4484 ◽

Cited By ~ 2

Author(s):

Murali Papudippu ◽

Hong Shu ◽

Sari Izenwasser ◽

Dean Wade ◽

Gerard Gulasey ◽

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Keyword(s):

Binding Affinity ◽

Receptor Binding ◽

Cannabinoid Receptor ◽

Regioselective Synthesis ◽

Receptor Binding Affinity

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A DFT and Semiempirical Model-Based Study of Opioid Receptor Affinity and Selectivity in a Group of Molecules with a Morphine Structural Core

International Journal of Medicinal Chemistry ◽

10.1155/2012/682495 ◽

2012 ◽

Vol 2012 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Tamara Bruna-Larenas ◽

Juan S. Gómez-Jeria

Keyword(s):

Binding Affinity ◽

Opioid Receptor ◽

Receptor Binding ◽

Kappa Opioid Receptor ◽

Kappa Opioid ◽

Receptor Binding Affinity ◽

Reactivity Indices ◽

Model Based ◽

Local Reactivity ◽

Opioid Receptor Binding

We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31 levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

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