Design, synthesis and structure–affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands
The design, synthesis and structure–affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands are described.
Introduction
The peripheral benzodiazepine receptor (PBR) has been found primarily as a high-affinity binding site for diazepam in rat kidney.1 In contrast to the central benzodiazepine receptor (CBR), which is associated with γ-aminobutyric acidA (GABAA)-regulated ion channels2 in the central nervous system,3, 4 PBR lacks coupling to GABAA receptors.
PBR has been found in many peripheral tissues,5, 6, 7 in blood cells7, 8 and in glial cells in the brain.7, 9, 10 Its primary localization has been reported to be mainly in the mitochondrial outer membranes in many tissues,11, 12, 13, 14 although PBR is located on the inner membrane of the rat lung mitochondria.13 Furthermore, PBR was also found on plasma membranes,7, 8 which lack mitochondria. Plasma membrane PBR has been described in heart, liver, adrenal, and testis and on hematopoietic cells.7
PBR is composed of at least three subunits, an isoquinoline binding subunit with a molecular mass of 18 kDa, a voltage-dependent anion channel (VDAC) with a molecular mass of 32 kDa and an adenine nucleotide carrier with a molecular mass of 30 kDa.15 cDNA encoding PBR has been cloned from humans,16 bovines,17 rats18 and mice.19 PBR plays roles in cell proliferation,20 steroidogenesis,21 calcium flow,22 cellular respiration,23 cellular immunity,24 and malignancy.25
As endogenous ligands for peripheral benzodiazepine receptors (PBRs), anthraline, diazepam-binding inhibitor (DBI) and proptoporphyrin IV have been reported. Anthraline, 16 kDa protein, binds to both PBR and the dihydropyridine binding sites.26 DBI, a 104 amino acid neuropeptide,27 has been found in human brain, and DBI-like immunoreactivity has been found in the cerebrospinal fluid of human volunteers.28 DBI has also been found in peripheral tissues rich in PBRs, such as adrenal gland, testis and kidney.29 The major physiological porphyrins, protoporphyrin IX and heme, have been labeled PBR with nanomolar affinity, and their affinity has been 1000 times higher for PBRs than for central benzodiazepine receptors (CBRs).30
PBR has exhibited different specificities for ligands. Compounds Chart 1, Figure 1 (Ro5-4864) and 2 (PK11195) exhibited high affinity for PBRs but not for CBRs,9, 31, 32 whereas compound 3 (clonazepam) exhibited low affinity for PBRs and high affinity for CBRs.33 Interestingly, in contrast to the highly species-dependent interaction of compound Chart 1, Figure 1 with PBRs,34, 35, 36, 37 compound 2 exhibited high affinity for PBRs from both humans and bovines.32 As other PBR ligands, compounds 4 (alpidem) and 5 (FGIN-1) have been reported. Compound 4 is an imidazopyridine derivative and binds with high affinity to both PBRs and CBRs.38 Compound 5 is a 2-aryl-3-indoleacetamide derivative and exhibits high affinity for PBRs with high selectivity over CBRs (Chart 1).39, 40
The physiological functions of PBR have not been fully elucidated, due in part to the lack of potent and selective ligands for PBRs. Our interest was concentrated on opening the diazepine ring of Chart 1, Figure 1 for discovering new PBR ligand since Chart 1, Figure 1 has more rigid structure than other PBR ligands such as 2, 4 and 5. We have presented potent and selective PBR ligands 7-096 (DAA1106) (PBR: IC50=0.28 nM, CBR: IC50>1000 nM) and 7-099 (DAA1097) (PBR: IC50=0.92 nM, CBR: IC50>1000 nM),41, 42, 43 compounds which were novel aryloxyanilide derivatives designed by opening the diazepine ring of Chart 1, Figure 1 (Fig. 1). Compound 7-096 is potent and selective ligand for PBRs since the binding of [3H]7-096 has not been affected by several neurotransmitter-related compounds, including adrenoceptor, γ-aminobutylic acid, dopamine, 5-hydroxytrypyamine, acetylcholine, histamine, glutamate and CBR ligands even at a concentration of 10 μM.42 Compounds 7-096 and 7-099 showed potent anxiolytic-like properties in laboratory animals.41 Furthermore, it has been suggested that (1) 7-096 and 7-099 binding sites on PBR share common domain with that of PK11195, but also contain motif that do not interact efficiently with PK11195; (2) these additional sites are par of the PBR molecular, since similar result are found using cells or recombinant PBR; (3) the binding of 7-099 to PBR induces changes in the receptor similar to that triggered by PK11195, allowing steroidogenesis activation; (4) the fact that 7-096 dose not activate steroidogenesis despite its high affinity for PBR suggests that its binding on PBR leads to conformational changes that do not permit or antagonize PBR steroidogenic function.43 Thus, aryloxyanilide derivatives are unique PBR ligands for studying the structure–function relationship of PBR.
In this paper, the design, synthesis and structure–affinity relationships of aryloxyanilide derivatives, which are novel PBR ligands, are presented.
Section snippets
Chemistry
The syntheses of derivatives 6, Figure 1, Scheme 1, 8 and 9 are shown in Scheme 1, Scheme 2, Scheme 3, Scheme. 4, Scheme 5, Scheme 6, Scheme 7, Scheme 8.
General synthetic methods for aryloxyanilide derivative Figure 1, Scheme 1 are indicated in Scheme 1.
Noncommercial 2-aryloxyaniline 11 was prepared by treatment of 2-halonitrobenzene 10 with hydroxyaryl compounds under basic conditions followed by hydrogenolysis (Method A) or reduction utilizing powdered Fe (Method B) (Table 1).
The
Results and discussion
Compounds Chart 1, Figure 1, 2, 5, 6, 7-001–Figure 1, Scheme 1, Scheme 2, Scheme 3, Scheme. 4, Scheme 5, Scheme 6, Scheme 7, Scheme 8, Figure 1, Scheme 1, Scheme 2, Scheme 3, Scheme. 4, Scheme 5, Scheme 6, Scheme 7, Scheme 8, 8 and Figure 1, Scheme 8 were evaluated for PBRs binding affinities in mitochondria prepared from rat cerebral cortex against radioligand [3H]-PK11195,41 and the obtained IC50 values are shown in Table 1. High-PBR-affinity compounds (IC50 <100 nM) among compounds 6, 7-001–
Conclusions
In this paper, we have reported the synthesis and SARs of 2-aryloxyanilide derivatives, which were obtained by ring-opening of Ro5-4864, as PBR ligands. Many 2-aryloxyanilide derivatives exhibited remarkably high affinity and selectivity for PBRs over CBRs. This successful design will have significant effects on the design of new PBR ligands. Furthermore, 2-aryloxyanilide derivatives can be used to probe the physiological functional roles of PBR. Interesting results of pharmacological studies
Experimental
Melting points were determined on a Yanaco MP-500D melting point apparatus and were uncorrected. Proton nuclear magnetic resonance (NMR) spectra were obtained using a Varian Gemini 2000 (200 MHz). Chemical shifts are reported in parts per million relative to tetramethylsilane as an internal standard. Several amide compounds were a mixture of E and Z isomers caused by the amide bond on NMR spectra. The ratio of E and Z isomers is reported as following: 3.63 (3H×3/4, s), 3.78 (3H×1/4, s). Mass
Acknowledgements
A part of synthetic research was carried out by M. Nagamine, K. Harada, K. Yamamoto and Dr. M. Yoshida (Research Division of Nihon Nohyaku Co., Ltd.). We wish to express our special thanks to them.
References (43)
- et al.
J. Biol. Chem.
(1992) - et al.
Biochem. Pharmacol.
(1996) - et al.
Eur. J. Pharmacol.
(1988) - et al.
J. Biol. Chem.
(1986) - et al.
J. Biol. Chem.
(1991) - et al.
J. Biol. Chem.
(1989) - et al.
Int. J. Immunopharmacol.
(1986) - et al.
Life Sci.
(1995) - et al.
Biochem. Pharmacol.
(1988) - et al.
Brain Res.
(1986)
Life Sci.
Bioorg. Med. Chem.
FEBS Lett.
Mol. Brain Res.
Brain Res.
Pharmacol. Biochem. Behav.
Life Sci.
Eur. J. Pharm.
Proc. Natl. Acad. Sci. U.S.A.
Science (Washington, DC)
Science (Washington, DC)
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