Pain management is an important medical problem with social and economic consequences. Opioid receptors are among the most important molecular targets involved in antinociception. We have previously reported several series of antinociceptive compounds with the affinity to opioid receptors. In search for novel compounds acting on central nervous system with antinociceptive activity we synthesized a series of 1-aryl-7-hydroxy-2,3-dihydroimidazo[1,2- a]pyrimidine-5(1H)-ones and their 6-phenyl derivatives. The novel compounds were subjected to extensive pharmacological studies to assess their effect on motor coordination, body temperature, clonic seizures and tonic convulsions and their antinociceptive activity. In the writhing test the antinociceptive activity of some derivatives was reversed by naloxone, thus we can assume that their activity may be associated with opioid system. We also used molecular modeling to describe active conformations of the studied compounds and to build a pharmacophore model. As in the previously reported series of the compounds, the studied substances exerted antinociceptive activity probably associated with the opioid system without possessing a protonable nitrogen atom. Furthermore, we calculated structural, electronic and ADMET parameters (volume, surface area, polar surface area, ovality, dipole moment, HOMO and LUMO energies, polarizaibility, molar refractivity, lipophilicity, the charges on the heteroatoms, aqueous solubility, and blood-brain barrier permeation parameter) for novel compounds in order to address the observed structure-activity relationship.

A series of 24 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones was designed as antinociceptive compounds acting through opioid receptors with additional serotoninergic activity. The compounds, similarly as previously published series, lack the protonable nitrogen atom which is a part of classical opioid receptor pharmacophore and is necessary to interact with the conserved Asp(3.32) in the opioid receptor binding pocket. The compounds were obtained in one-step cyclocondensation of 1-aryl-4,5-dihydro-1H-imidazol-2-amines diethyl 2-benzylmalonate or diethyl 2-(2-chlorobenzyl)malonate under basic conditions. Almost all the tested compounds exerted strong antinociceptive activity, but surprisingly, it was not reversed by naloxone; thus, it is not mediated through opioid receptors. It makes it possible to conclude that addition of one more aromatic moiety to the non-classical opioid receptor pharmacophore results in the compounds which are not opioid receptor ligands. The lack of activity of one of the tested compounds may be attributed to low blood–brain barrier permeation or unfavorable distribution of electrostatic potential and HOMO and LUMO orbitals.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-014-0993-1) contains supplementary material, which is available to authorized users.

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