A general model of the opiate pharmacophore 1. Regions of the opiate pharmacophore responsible for nonselective affinity for the opiate receptor

Abstract

By superposition of the molecules of opiate receptor ligands of various structural classes, three regions responsible for the nonselective ligand affinity were distinguished in the opiate pharmacophore. Spatial arrangement features, electronic properties, the capability of H bond ing and hydrophobic and electrostatic interactions of these regions were determined. The set of geometric parameters found can be used as a criterion for estimation of the opiate activity in simulation of new types of ligands.Key words: opiate receptor ligands, nonselective binding to opiate receptors, a model of the opiate pharmacophore, superposition of molecules.Successful prediction of the "structure-biological ac tivity" relationships should rely on comprehensive infor mation about the pharmacophore, including the set of spatial and electronic features that ensure the supra molecular interactions with the structure of a specific biological target and actuate its biological response. Numerous studies devoted to the structures of opiate pharmacophore (OP) have been carried out. Most often, a set of definite functional groups or typical structural fragments that are distinguished by superposition of opi ate active molecules is proposed as an OP model. The proposed OP models are applicable to either particular structural classes of ligands of opiate receptors (OR) 1-4 or to ligands exhibiting a certain selectivity with respect to OR (see Ref. 5). No general model of OP applicable to all types of OR ligands irrespective of the structural class of the ligand, selectivity of its action on receptors, or the ratio of agonistic/antagonistic properties has been re ported.This study continues the systematic investigation into the structure of OP aimed at the development of a general model of OP not as a set of particular functional groups but a set of some abstractive molecular regions arranged in space in a particular manner and having particular electronic properties. This model will be described by a set of pharmacophore descriptors determining the spatial arrangement of the binding sites of the ligand with the OR, the tendency for H bonding, hydrophobic and electro static interactions, etc.Previously, we have demonstrated that OR ligands can exist as two bioactive conformations (I and II) differ ing in the mutual orientations of the key structural frag ments of OR ligand molecules, namely, the protonated amino group and the phenyl ring. 6 These structural frag ments are responsible for the ligand affinity for OR (elec trostatic interaction of the protonated nitrogen atom with the anionic group of the complementary OR region supplemented by hydrogen bonding 7-10 and π-π inter action of the phenyl fragment with a particular comple mentary section of OR as the electron density donor 11 ). The existence of conformations of I and II does not de pend on the structural class of the ligand, the selectivity of its action on receptors, or the ratio of agonistic/antago nistic properties. Each conformation is described by its own set of geometric param...

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

“…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).…”

“…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).…”

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

“…However, there exist high-probability regions that are primarily sampled by agonists versus antagonists and vice versa for both the peptide and nonpeptide ligands. Kuz'mina et al presented in a series of papers a general model of the opiate pharmacophore [ 8 – 10 ]. Bernard et al extended the CSP method to obtain quantitative models of δ opioid ligand efficacy and affinity [ 11 ].…”