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Synthesis, central nervous system activity, and structure-activity relationship of 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones.

Rządkowska M, Szacoń E, Kaczor AA, Fidecka S, Kędzierska E, Matosiuk D - Med Chem Res (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St, 20093 Lublin, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

The influence of the tested compounds on the head-twitch responses evoked by L-5-HTP (230 mg/kg). The results are expressed as mean ± SEM of a group of eight mice. One-way ANOVA showed significant changes in the number of head-twitch episodes (F7,56 = 4.879, p < 0.001). The post-hoc Tukey’s test confirmed a significant decrease in the numer of head-twitch episodes after the administration of the following compounds in the dose of 0.1 ED50: 3n (p < 0.001), 3d (p < 0.01), and 3a, 3g, and 3s (p < 0.05)
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Fig8: The influence of the tested compounds on the head-twitch responses evoked by L-5-HTP (230 mg/kg). The results are expressed as mean ± SEM of a group of eight mice. One-way ANOVA showed significant changes in the number of head-twitch episodes (F7,56 = 4.879, p < 0.001). The post-hoc Tukey’s test confirmed a significant decrease in the numer of head-twitch episodes after the administration of the following compounds in the dose of 0.1 ED50: 3n (p < 0.001), 3d (p < 0.01), and 3a, 3g, and 3s (p < 0.05)

Mentions: The tested compounds only slightly affected body temperature of mice: used in a dose equivalent to 0.1 ED50 significantly lowered it, but only in 30-min of observation, and used at twice less dose increased it (3p and 3s) or have no effect (the others). Almost all tested compounds (except 3l and 3p) and to varying degrees (the strongest effect for 3n compound, p < 0.001) suppressed L-5-HTP-induced head-twitch episodes (Fig. 8), suggesting some connections with serotonin system. The tested substances failed to protect against clonic seizures, tonic convulsions, and death in PTZ-induced model of seizures.Fig. 8


Synthesis, central nervous system activity, and structure-activity relationship of 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones.

Rządkowska M, Szacoń E, Kaczor AA, Fidecka S, Kędzierska E, Matosiuk D - Med Chem Res (2014)

The influence of the tested compounds on the head-twitch responses evoked by L-5-HTP (230 mg/kg). The results are expressed as mean ± SEM of a group of eight mice. One-way ANOVA showed significant changes in the number of head-twitch episodes (F7,56 = 4.879, p < 0.001). The post-hoc Tukey’s test confirmed a significant decrease in the numer of head-twitch episodes after the administration of the following compounds in the dose of 0.1 ED50: 3n (p < 0.001), 3d (p < 0.01), and 3a, 3g, and 3s (p < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127001&req=5

Fig8: The influence of the tested compounds on the head-twitch responses evoked by L-5-HTP (230 mg/kg). The results are expressed as mean ± SEM of a group of eight mice. One-way ANOVA showed significant changes in the number of head-twitch episodes (F7,56 = 4.879, p < 0.001). The post-hoc Tukey’s test confirmed a significant decrease in the numer of head-twitch episodes after the administration of the following compounds in the dose of 0.1 ED50: 3n (p < 0.001), 3d (p < 0.01), and 3a, 3g, and 3s (p < 0.05)
Mentions: The tested compounds only slightly affected body temperature of mice: used in a dose equivalent to 0.1 ED50 significantly lowered it, but only in 30-min of observation, and used at twice less dose increased it (3p and 3s) or have no effect (the others). Almost all tested compounds (except 3l and 3p) and to varying degrees (the strongest effect for 3n compound, p < 0.001) suppressed L-5-HTP-induced head-twitch episodes (Fig. 8), suggesting some connections with serotonin system. The tested substances failed to protect against clonic seizures, tonic convulsions, and death in PTZ-induced model of seizures.Fig. 8

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, 4A Chodźki St, 20093 Lublin, Poland.

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.

No MeSH data available.


Related in: MedlinePlus