A Theoretical Structure-Affinity Relationship Study of Some Cannabinoid Derivatives

Abstract

A ZINDO/1 quantum-chemical structure-affinity relationship study with the KPG model is presented for the in vitro interaction of a group of classical, indolederived and aminoalkylindole-derived cannabinoids with CB 1 and CB 2 receptors. From this work the following conclusions are obtained. CB 1 and CB 2 CB 2 receptor affinities are regulated by different mechanisms involving orbital and charge control. Nevertheless CB 1 and CB 2 classical ligands share three common features: a hydrogen bond to a lysine (for CB 1 ) or serine (for CB 2 ), a fully aromatic ring and a branched carbon side chain. In the case of indole-derived and aminoalkylindolederived cannabinoids orientation and alignment rules have been defined as a basis for the comparison of noncongeneric molecules. In this way it was possible to associate the location of molecular fragments of these systems with known molecular systems such as classical cannabinoids. For aminoalkylindoles we have proposed the locus with which they bind to a second receptor site that is available to WIN-55212-2 but not to classical cannabinoids. On the basis of our results we propose a new molecule that should help to discriminate between the above two receptor sites.

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

“…We have called them orientational parameters 49 . This model has shown, beyond all reasonable doubt, that it can shed light on the detailed structure of the drugreceptor interaction for several kind of biomolecules and receptors 48,[56][57][58][59][60][61][62][63][64][65][66] , that it has predictive capacity [67][68][69] and is even able to detect erroneous experimental data 70 . The last paper employing this method and not belonging to our group was published in 1979 71 .…”

A DFT Study of the Relationships Between Electronic Structure and Peripheral Benzodiazepine Receptor Affinity in a Group of N,n-Dialkyl-2-Phenylindol-3-Ylglyoxylamides

“…F i (m) is the Fukui function of atom i at MO m (or m'). The whole family of Fukui indices has been employed in our group for more than 20 years in structure-activity studies [2][3][4][5][6][7][8][9][10][11][12][13][14] .…”

Quantum-chemical Modeling of the Relationships between Molecular Structure and In Vitro Multi-Step, Multimechanistic Drug Effects. HIV-1 Replication Inhibition and Inhibition of Cell Proliferation as Examples

“…The whole process is orbital-controlled [36]. A high value of 11 ( 2)* E S HOMO  is required for optimal antiproliferative activity. The (HOMO)* for atom 11 is of π nature in all the molecules.…”

“…During the last three decades we have developed a formal method [1] to correlate in vitro receptor binding affinity constants with the electronic structure and substituent orientational parameters of drug molecules [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. A formal or non-empirical method is based on the following philosophy: it begins by proposing a model to explain a given biological activity.…”