Limits...
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

HOMO (a, c) and LUMO (b, d) orbitals for 3a (a, b) and 3l (c, d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4127001&req=5

Fig9: HOMO (a, c) and LUMO (b, d) orbitals for 3a (a, b) and 3l (c, d)

Mentions: The lack of activity of compound 3l may be connected with the low blood–brain permeation. Furthermore, the presence of benzyl not phenyl substituent at the nitrogen N1 atom orients the pharmacophoric aromatic ring differently and it may constitute another explanation of the lack of acivity of 3l. In order to further investigate the lack of activity of this componds, some structural and electronic parameters were calculated (Table 3). Compounds 3l and 3x have the greatest value of HOMO–LUMO gap. Furthermore, the map of HOMO and LUMO orbitals for the inactive compound 3l is slightly different than for the acive compound 3a (Fig. 9). The same concerns the distribution of electrostatic potential (Fig. 10). Next, compound 3l belongs to the biggest compounds of the series and may be literally to expanded to fit to the binding pocket of the potential molecular targets. Values of polar surface area and polarizability cannot be connected with the lack of activity of 3l.Table 3


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)

HOMO (a, c) and LUMO (b, d) orbitals for 3a (a, b) and 3l (c, d)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig9: HOMO (a, c) and LUMO (b, d) orbitals for 3a (a, b) and 3l (c, d)
Mentions: The lack of activity of compound 3l may be connected with the low blood–brain permeation. Furthermore, the presence of benzyl not phenyl substituent at the nitrogen N1 atom orients the pharmacophoric aromatic ring differently and it may constitute another explanation of the lack of acivity of 3l. In order to further investigate the lack of activity of this componds, some structural and electronic parameters were calculated (Table 3). Compounds 3l and 3x have the greatest value of HOMO–LUMO gap. Furthermore, the map of HOMO and LUMO orbitals for the inactive compound 3l is slightly different than for the acive compound 3a (Fig. 9). The same concerns the distribution of electrostatic potential (Fig. 10). Next, compound 3l belongs to the biggest compounds of the series and may be literally to expanded to fit to the binding pocket of the potential molecular targets. Values of polar surface area and polarizability cannot be connected with the lack of activity of 3l.Table 3

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