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. 1. Introduction Cannabis has a long history of association with mankind [1]. Probably it was used for medical purposes before recorded history. The cultic use of Cannabis seems to have been an extended practice ranging from Rumania east to the Yenisei River from at least the third millennium BC [2–8]. Cannabis originated in northern South Asia along the foothills of the Himalayas or the valley of Central Asia. It was first cultivated on a large scale basis in China for fiber and seed production and later in India for resin production. Its cultivation spread from China and India to other places of the world. In 1545 the Spanish brought Cannabis to the New World. From the taxonomic point of view, two classes of plants are discernible: a group of plants with relatively limited intoxicant potential, obtained by selection for fiber and oil agronomic qualities, and another group with considerable intoxicant potential, obtained by selection for inebriant qualities. These two groups are classified as subspecies sativa and indica, of C. sativa, the only species of the genus Cannabis. Within each subspecies wild and domesticated phases can be recognized. These four groups are recognized as varieties [9–15]. Marijuana consists of a mixture of leaves, stems, and flowering tops of Cannabis plants selectively bred to produce high levels of Δ9-tetrahydrocannabinol (THC or (？)-trans-Δ9-THC) and several other psychoactive cannabinoids. Various extracts including hashish and hash oil are also produced from the plant. Muslims used Cannabis recreationally because alcohol consumption
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