Development of concepts on the interaction of drugs with opioid receptors

Method for estimating a compound’s opiate activity based on a versatile three-dimensional model of nonselective opiate pharmacophore

“…This term reflects the current changes in the concept of pharmacophore (we described the evolution of the pharmacophore concept in review [8]), and is introduced to characterize the spatial fea tures that are necessary for optimal interaction with the receptor structure. The pharmacophore area is a region of space occupied by functionally equivalent structural fragments of bioactive molecules involved in the same type of interaction with the biotarget.…”

“…Before the discovery of opiate activity in flavonoids [23] and trans neoclerodane diterpenoids [24], it was assumed that the presence of a positively charged nitrogen atom in opioids is an absolute requirement for their interaction with ORs [24,43]. In the affine areas В and С, the interaction with charge transfer supplemented by hydrogen bonding occurs (the ligand is a donor of electron density); and in agonistic areas D and E the hydrophobic interaction takes place; in the antagonistic area F either hydrophobic interac tions or hydrogen bonding occur, and the type of antagonistic interaction affects the ligand selectivity [27]. The affine interactions in pharmacophore areas А (H bond), В, and С (charge transfer) are directional.…”

“…A detailed descrip tion of the construction of some of its separate frag ments is presented in [25][26][27], the comparison of the technologies for constructing our model and its pub lished analogues is given in the review [8]. We used the conformationally restricted ligands, such as 4,5 epoxymorphinans, dihydromorpnones, morphinans, benzomorphinans, oripavines, spiro[benzofuran 3(2H),4' piperidines], 5 arylmorphanes, tropane and isoquinoline derivatives, and the 4 phenylpiperidine molecules with the fixed cycle conformation and con figuration of chiral centers, as a training set (a total of 125 compounds).…”

“…On the basis of the concept of the existence of two ligand positions in the reception zone, we have pro posed to classify pharmacophore areas as affine, ago nistic, and antagonistic depending on the specific fea tures being implemented in the areas of ligand-recep tor interactions [25][26][27]. Interactions responsible only for the receptor recognition, i.e., common for agonists and antagonists, are realized in the affine pharma cophore areas (e.g., the interaction of a protonated nitrogen atom of the ligand with AspIII:7 of ORs).…”

“…The assessment of opiate activity of any compound is performed on the basis of compari son of its electronic and spatial characteristics with the corresponding characteristics of the 3D pharmaco phore model. A comparative analysis of the literature of OP models is presented in the review [8].…”