Three-Dimensional Quantitative Structure−Activity Relationship Study of the Cannabimimetic (Aminoalkyl)indoles Using Comparative Molecular Field Analysis

Abstract

The present study describes the implementation of comparative molecular field analysis (CoMFA) to develop two 3D-QSAR (quantitative structure-activity relationship) models (CoMFA models 1 and 2) of the cannabimimetic (aminoalkyl)indoles (AAIs) for CB1 cannabinoid receptor binding affinity, based on pKi values measured using radioligand binding assays that displace two different agonist ligands, [3H]CP-55940 and [3H]WIN-55212-2. Both models exhibited a strong correlation between the calculated steric-electrostatic fields and the observed biological activity for the respective training set compounds. In light of the basicity of the morpholine nitrogen in the AAIs, separate CoMFA models were built for the AAIs as unprotonated and protonated species. Comparison of the statistical parameters resulting from these CoMFA models failed to provide unequivocal evidence as to whether the AAIs are protonated or neutral as receptor-bound species. Although the training sets of CoMFA model 1 and CoMFA model 2 differed with respect to composition and to the choice of displacement radioligand in each biological assay, their CoMFA StDevCoeff contour plots reveal similarities in terms of identifying those regions around the AAIs that are important for CB1 cannabinoid receptor binding such as the sterically favored region around the C3 aroyl group and the sterically forbidden region around the indole ring. When the experimental pKi values for the training set compounds to displace the AAI radioligand [3H]WIN-55212-2 were plotted against the pKi values as predicted for the same compounds to displace the cannabinoid radioligand [3H]CP-55940, the correlation was moderately strong (r = 0.73). However, the degree of correlation may have been lowered by the structural differences in the compounds comprising the training sets for CoMFA model 1 and CoMFA model 2. Taken together, the results of this study suggest that the binding site region within the CB1 cannabinoid receptor can accommodate a wide range of structurally diverse cannabimimetic analogues including the AAIs.

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

“…Our results further suggest that cannabinoid agonist structure may also play a key role in the coupling of CB 1 to G-proteins of both the G q/11 and G i/o classes. Cannabinoid receptor agonists occupy a common binding region within the CB 1 receptor, as demonstrated by their mutual competitive displacement in both radioligand binding assays (Showalter et al, 1996;Felder et al, 1998;Horn et al, 2003) and structure-activity relationship modelling (Shim et al, 1998). However; within the hypothesized binding region, mutagenesis (Song and Bonner, 1996;Chin et al, 1998;McAllister et al, 2003) and molecular modelling (Reggio, 2005;Shim and Howlett, 2006) have demonstrated that the aminoalkylindoles interact with a series of residues distinct from those targeted by classical, non-classical and eicosanoid agonists.…”

Study on Conformation Interconversion of 3-Alkyl-4-acetyl-3,4-dihydro-2H-1,4-benzoxazines from Dynamic NMR Experiments and ab Initio Density Functional Calculations

“…At each theoretical level, the changing tendency of the ∆G i values is in fine accordance with the experimental findings even though the changing speed may differ greatly, which may be controlled by the current theoretical levels. MP2 seems to have no substantial advantage over B3LYP, probably a result of intramolecular hydrogen bonding involved in our system instead of intermolecular hydrogen bonding in the system of Costa et al 26 Supposing that DMSO-d 6 would not freeze at 229 K, we calculated the activation free energies at 229, 269, and 316 K. It is shown that, at each specified temperature, the activation free energy is smaller in DMSO-d 6 than in CDCl 3 . The interconversion rate in DMSO-d 6 is about 1.5 times faster than that in CDCl 3 (see Table 1).…”

“…In CDCl 3 , the coalescence temperatures for H 3 and H 19 are 316 and 304 K. Accordingly, we should have observed the coalescence phenomena in DMSO-d 6 through the variabletemperature NMR experiments from 296 to 375 K. However, no such trace was captured from either 1 H or 13 C NMR spectra (see Figures S1 or S2 of Supporting Information). This may be a result of the faster interconversion rate in DMSO-d 6 than in CDCl 3 . As a result, the coalescence temperature for the same H is lower in DMSO-d 6 than in CDCl 3 .…”

“…[1][2][3][4] Following the conventional and economical synthesis route reported by Kundu et al, 5 we have successfully obtained a number of novel optically active 3-alkyl-3,4-dihydro-2H-benzo [1,4]oxazine derivatives, as presented in Scheme 1. 6 The dynamic NMR technique has been well-acknowledged as being powerful enough to investigate the conformation interconversions, acquiring information such as coalescence temperatures, activation free energies, and exchange rates.…”

“…First, in this study, variable-temperature NMR experiments were performed in two solvents, chloroform (CDCl 3 ) and dimethyl sulfoxide (DMSO-d 6 ). The conformation interconversion was investigated in CDCl 3 , which has a lower freezing point, with the activation free energies and interconversion rates obtained at each temperature. The assignments of 1 H and 13 C NMR spectra were completed in DMSO-d 6 , which has a higher boiling point.…”