Abstract
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.
Highlights
The treatment of central nervous system diseases in European Union costs 386 billion euro per year, placing these diseases among the most costly medical conditions (Di Luca et al, 2011)
The compounds, 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
Almost all the tested compounds exerted strong antinociceptive activity, but surprisingly, it was not reversed by naloxone; it is not mediated through opioid receptors
Summary
The treatment of central nervous system diseases in European Union costs 386 billion euro per year, placing these diseases among the most costly medical conditions (Di Luca et al, 2011). Many morphine-like narcotic analgesics share in their structure similar features, which are the phenyl ring, tertiary nitrogen atom, and the two carbon fragment (e.g., as a part of the piperidine ring). This classical opioid pharmacophore model was one of the first models used to explain the antinociceptive activity of morphine derivatives. The main finding of the studies is that all the investigated compounds exhibited strong antinociceptive properties, this activity was not reversed by naloxone; it is not mediated through opioid receptors
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