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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 pharmacophore model for the affinity to 5-HT2 receptor (Matosiuk et al., 2002b) consisting of an aromatic moiety and two hydrogen bond acceptors
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Fig3: The pharmacophore model for the affinity to 5-HT2 receptor (Matosiuk et al., 2002b) consisting of an aromatic moiety and two hydrogen bond acceptors

Mentions: 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). In particular, treatment of pain is an extremely important medical problem with social and economic implications. Searching for new antinociceptive agents follows nowadays two main strategies: exploitation of well-established targets, such as opioid receptors (Kaczor and Matosiuk, 2002a, b) or identification of novel molecular targets. In our continuous efforts to find novel antinociceptive agents, we synthesized and studied several series of novel heterocyclic compounds acting through opioid receptors, Fig. 1 (Matosiuk et al., 2001, 2002a, b; Sztanke et al., 2005). 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. Interestingly, the compounds presented in Fig. 1, similarly as salvinorin A (a potent κ opioid receptor ligand) do not possess a protonable nitrogen atom, capable to interact with the conserved aspartate residue (Asp3.32) in the receptor binding pocket. Instead, these compounds follow the non-classical opioid receptor pharmacophore models as presented in Fig. 2, which involve a base (B), a hydrophobic (H) and aromatic moiety (Ar) or hydrogen bond acceptor (HA), hydrophobic (H), and aromatic groups (Ar) (Huang et al.,1997; Matosiuk et al., 2001, 2002a, 2002b; Sztanke et al., 2005). In addition to the antinociceptive activity, some of the compounds presented in Fig. 1 exhibited also serotoninergic activity and affinity to 5-HT2 serotonin receptor. It was proposed that two hydrogen bond donors and the aromatic moiety are required for the serotoninergic activity as presented in Fig. 3 (Matosiuk et al., 2002b).Fig. 1


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 pharmacophore model for the affinity to 5-HT2 receptor (Matosiuk et al., 2002b) consisting of an aromatic moiety and two hydrogen bond acceptors
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: The pharmacophore model for the affinity to 5-HT2 receptor (Matosiuk et al., 2002b) consisting of an aromatic moiety and two hydrogen bond acceptors
Mentions: 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). In particular, treatment of pain is an extremely important medical problem with social and economic implications. Searching for new antinociceptive agents follows nowadays two main strategies: exploitation of well-established targets, such as opioid receptors (Kaczor and Matosiuk, 2002a, b) or identification of novel molecular targets. In our continuous efforts to find novel antinociceptive agents, we synthesized and studied several series of novel heterocyclic compounds acting through opioid receptors, Fig. 1 (Matosiuk et al., 2001, 2002a, b; Sztanke et al., 2005). 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. Interestingly, the compounds presented in Fig. 1, similarly as salvinorin A (a potent κ opioid receptor ligand) do not possess a protonable nitrogen atom, capable to interact with the conserved aspartate residue (Asp3.32) in the receptor binding pocket. Instead, these compounds follow the non-classical opioid receptor pharmacophore models as presented in Fig. 2, which involve a base (B), a hydrophobic (H) and aromatic moiety (Ar) or hydrogen bond acceptor (HA), hydrophobic (H), and aromatic groups (Ar) (Huang et al.,1997; Matosiuk et al., 2001, 2002a, 2002b; Sztanke et al., 2005). In addition to the antinociceptive activity, some of the compounds presented in Fig. 1 exhibited also serotoninergic activity and affinity to 5-HT2 serotonin receptor. It was proposed that two hydrogen bond donors and the aromatic moiety are required for the serotoninergic activity as presented in Fig. 3 (Matosiuk et al., 2002b).Fig. 1

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