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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 spontaneous locomotor activity of mice. The results are expressed as mean ± SEM of a group of 6–14 mice. One-way ANOVA showed significant changes in locomotor activity of mice after the administration of the compound 3a (F3,29 = 5.999, p < 0.01), 3d (F4,35 = 4.942, p < 0.01), 3g (F3,31 = 5.6, p < 0.01), 3l (F2,25 = 3.361, p = 0.051) and 3n (F4,37 = 6.596, p < 0.001). Post-hoc Tukey’s test confirmed a significant reduction in motility of mice after the administration of the compound 3a in the dose of 0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3d—0.1 ED50 (p < 0.01), 0.05, and 0.025 ED50 (appropriately p < 0.05, p < 0.01), 3g—0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3l—0.1 ED50 (p < 0.05) and 3n—0.1, 0.05, and 0.025 ED50 (p < 0.01)
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Fig7: The influence of the tested compounds on the spontaneous locomotor activity of mice. The results are expressed as mean ± SEM of a group of 6–14 mice. One-way ANOVA showed significant changes in locomotor activity of mice after the administration of the compound 3a (F3,29 = 5.999, p < 0.01), 3d (F4,35 = 4.942, p < 0.01), 3g (F3,31 = 5.6, p < 0.01), 3l (F2,25 = 3.361, p = 0.051) and 3n (F4,37 = 6.596, p < 0.001). Post-hoc Tukey’s test confirmed a significant reduction in motility of mice after the administration of the compound 3a in the dose of 0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3d—0.1 ED50 (p < 0.01), 0.05, and 0.025 ED50 (appropriately p < 0.05, p < 0.01), 3g—0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3l—0.1 ED50 (p < 0.05) and 3n—0.1, 0.05, and 0.025 ED50 (p < 0.01)

Mentions: All other tested compounds exerted significant antinociceptive activity in the writhing test (Fig. 6a, b). The effect was strong for all of the compounds and remained until the dose equivalent to 0.025 ED50. In the case of compound 3p, a significant reduction in number of writhing episodes was also observed, when the compound was used at a lower dose of 0.0125 ED50. However, we observed significant impairment of motor coordination in the rota-rod test after dose of 0.1 ED50 of this compound, what can hinder the interpretation of this result as a significant analgesic effect. On the other hand, the administration of the compound 3p did not cause any change in the spontaneous locomotor activity of the animals (Fig. 7), which would indicate that the compound 3p disturbing coordination, does not change the motor activity. The antinociceptive activity of the tested compounds does not appear to be associated with endogenous opioid system because naloxone (5 mg/kg) nonselective opioid receptor antagonist did not alter the observed effects (data not presented).Fig. 6


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 spontaneous locomotor activity of mice. The results are expressed as mean ± SEM of a group of 6–14 mice. One-way ANOVA showed significant changes in locomotor activity of mice after the administration of the compound 3a (F3,29 = 5.999, p < 0.01), 3d (F4,35 = 4.942, p < 0.01), 3g (F3,31 = 5.6, p < 0.01), 3l (F2,25 = 3.361, p = 0.051) and 3n (F4,37 = 6.596, p < 0.001). Post-hoc Tukey’s test confirmed a significant reduction in motility of mice after the administration of the compound 3a in the dose of 0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3d—0.1 ED50 (p < 0.01), 0.05, and 0.025 ED50 (appropriately p < 0.05, p < 0.01), 3g—0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3l—0.1 ED50 (p < 0.05) and 3n—0.1, 0.05, and 0.025 ED50 (p < 0.01)
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Related In: Results  -  Collection

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Fig7: The influence of the tested compounds on the spontaneous locomotor activity of mice. The results are expressed as mean ± SEM of a group of 6–14 mice. One-way ANOVA showed significant changes in locomotor activity of mice after the administration of the compound 3a (F3,29 = 5.999, p < 0.01), 3d (F4,35 = 4.942, p < 0.01), 3g (F3,31 = 5.6, p < 0.01), 3l (F2,25 = 3.361, p = 0.051) and 3n (F4,37 = 6.596, p < 0.001). Post-hoc Tukey’s test confirmed a significant reduction in motility of mice after the administration of the compound 3a in the dose of 0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3d—0.1 ED50 (p < 0.01), 0.05, and 0.025 ED50 (appropriately p < 0.05, p < 0.01), 3g—0.1 ED50 (p < 0.05) and 0.05 ED50 (p < 0.01), 3l—0.1 ED50 (p < 0.05) and 3n—0.1, 0.05, and 0.025 ED50 (p < 0.01)
Mentions: All other tested compounds exerted significant antinociceptive activity in the writhing test (Fig. 6a, b). The effect was strong for all of the compounds and remained until the dose equivalent to 0.025 ED50. In the case of compound 3p, a significant reduction in number of writhing episodes was also observed, when the compound was used at a lower dose of 0.0125 ED50. However, we observed significant impairment of motor coordination in the rota-rod test after dose of 0.1 ED50 of this compound, what can hinder the interpretation of this result as a significant analgesic effect. On the other hand, the administration of the compound 3p did not cause any change in the spontaneous locomotor activity of the animals (Fig. 7), which would indicate that the compound 3p disturbing coordination, does not change the motor activity. The antinociceptive activity of the tested compounds does not appear to be associated with endogenous opioid system because naloxone (5 mg/kg) nonselective opioid receptor antagonist did not alter the observed effects (data not presented).Fig. 6

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