Synthesis, Biological Evaluation, and Receptor Docking Simulations of 2-[(Acylamino)ethyl]-1,4-benzodiazepines as κ-Opioid Receptor Agonists Endowed with Antinociceptive and Antiamnesic Activity

Abstract

The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical and pharmacological studies on compounds 6 have been pursued with the aim of expanding the SAR data and validating the previously proposed model of interaction of this class of compounds with the kappa-opioid receptor. The synthesis of the previously described compounds 6 has been reinvestigated in order to obtain a more direct synthetic procedure. To study the relationship between the stereochemistry and the receptor binding affinity, compounds 6e and 6k were selected on the basis of their evident structural resemblance to tifluadom. Since a different specificity of action could be expected for the enantiomers of 6e and 6k, owing to the results shown by (S)- and (R)-tifluadom, their racemic mixtures have been resolved by means of liquid chromatography with chiral stationary phases (CSP), and the absolute configuration of the enantiomers has been studied by circular dichroism (CD) and (1)H NMR techniques. Moreover, some new 2-[(acylamino)ethyl]-1,4-benzodiazepine derivatives, 6a-d,f,g,j, have been synthesized, while the whole series (6a-o) has been tested for its potential affinity toward human cloned kappa-opioid receptor. The most impressive result obtained from the binding studies lies in the fact that this series of 2-[2-(acylamino)ethyl]-1,4-benzodiazepine derivatives binds the human cloned kappa-opioid receptor subtype very tightly. Indeed, almost all the ligands within this class show subnanomolar K(i) values, and the least potent compound 6o shows, in any case, an affinity in the nanomolar range. A comparison of the affinities obtained in human cloned kappa-receptor with the correspondent one obtained in native guinea pig kappa-receptor suggests that the human cloned kappa-receptor is less effective in discriminating the substitution pattern than the native guinea pig kappa-receptor. Furthermore, the results obtained are discussed with respect to the interaction with the homology model of the human kappa-opioid receptor, built on the recently solved crystal structure of rhodopsin. Finally, the potential antinociceptive and antiamnesic properties of compounds 6e and 6i have been investigated by means of the hot-plate and passive avoidance test in mice, respectively.

Acylation of Meldrum’s acid with arylacetic acid imidazolides as a convenient method for the synthesis of 4-aryl-3-oxobutanoates

“…Arylacetic acid 1c was obtained by Wilgerodt-Kindler's reaction from 3 acetyl 2,5 dimethylthiophene, 24 and acid 1f was prepared by reduction of ethyl 2 (2 methylbenzothiophen 3 yl) 2 oxoacetate with tri ethylsilane. 25 Preparation of keto esters 4 (general procedure). A.…”

Novel Ester and Acid Derivatives of the 1,5-Diarylpyrrole Scaffold as Anti-Inflammatory and Analgesic Agents. Synthesis and in Vitro and in Vivo Biological Evaluation

“…The construction of the C3 side chain was achieved by regioselective acylation of 14a,c,e,g with oxalyl chloride in the presence of 2,6-lutidine to give corresponding R-keto acid chlorides that, by the successive reaction in the presence of the proper alcohol, gave the corresponding R-keto ester derivatives 15a-h in a one-pot reaction. Compounds 15a-h were in turn reduced by means of triethylsilane in trifluoroacetic acid to give the pyrrole esters 10a-h. 30 Construction of the C3 acetic acid chain of 6a and 11c,e,g was achieved by regioselective acylation of 14a,c,e,g with ethoxalyl chloride in the presence of titanium tetrachloride to give corresponding R-keto esters 16a,c,e,g in turn reduced (triethylsilane in trifluoroacetic acid) Scheme 1 a a Compounds: 10a, R = H, R 1 = isopropyl, 55% yield; 10b, R = H, R 1 = n-butyl, 50% yield; 10c, R = 3-F, R 1 = isopropyl, 96% yield; 10d, R = 3-F, R 1 = n-butyl, 40% yield; 10e, R = 3,4-diF, R 1 = isopropyl, 45% yield; 10f, R = 3,4-diF, R 1 = n-butyl, 40% yield; 10g, R = 4-OCH 3 , R 1 = isopropyl, 40% yield; 10h, R = 4-OCH 3 , R 1 = n-butyl, 40% yield; 6a, R = H, 71% yield; 11c, R = 3-F, 60% yield; 11e, R = 3,4-diF, 75% yield; 11g, R = 4-OCH 3 , 70% yield; 14a, R = H, 80% yield; 14c, R = 3-F, 80% yield; 14e, R = 3,4-diF, 74% yield; 14g, R = 4-OCH 3 , 70% yield; 15a, R = H, R 1 = isopropyl, 76% yield; 15b, R = H, R 1 = n-butyl, 90% yield; 15c, R = 3-F, R 1 = isopropyl, 40% yield; 15d, R = 3-F, R 1 = n-butyl, 55% yield; 15e, R = 3,4-diF, R 1 = isopropyl, 77% yield; 15f, R = 3,4-diF, R 1 = n-butyl, 65% yield; 15g, R = 4-OCH 3 , R 1 = isopropyl, 40% yield; 15h, R = 4-OCH 3 , R 1 = n-butyl, 60% yield; 16a, R = H, 76% yield; 16c, R = 3-F, 57% yield; 16e, R = 3,4-diF, 77% yield; 16g, R = 4-OCH 3 , 75% yield; 17a, R = H, 71% yield; 17c, R = 3-F, 45% yield; 17e, R = 3,4-diF, 60% yield; 17g, R = 4-OCH 3 to the pyrrole acetic esters 17a,c,e,g that led to the corresponding acids 6a and 11a,c,e,g by treatment with 1 N NaOH in MeOH for 1 h.…”

Target Profile Prediction: Cross‐Activation of Peroxisome Proliferator‐Activated Receptor (PPAR) and Farnesoid X Receptor (FXR)

“…Pseudoreceptor model of compound 1 (gray) aligned with potent and subtype-selective opioid receptor agonists 3 (d: IC 50 = 0.87 nM; orange) [42] and 4 (k: IC 50 = 0.7 nM; magenta). [43] Potential receptor interaction sites are shown as colored spheres (green: aromatic, blue: hydrogen-bond donor). For each compound, one CORINA [44] conformation was generated and a PRPS [18] pseudoreceptor model computed.…”