A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids

Hernández-Gallegos, Zurisaddai; Lehmann, Anne

doi:10.1021/jm00172a021

Cited by 11 publications

(7 citation statements)

References 2 publications

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“…Some of them (# 8 and 9) contribute virtually nothing but instead exert their influence through the previously mentioned cross-terms. The calculated activities of the test set of data set A (42-46) are also generally closer to the experimental ones than obtained in reference [6] ( Table 2). B (1-46) made little difference compared to data set A (r2 = 0.81, cross-validated r2 = 0.74, s = 0.258, F = 59.21).…”

Section: Discussionsupporting

confidence: 80%

“…Adding cross-terms, which reflect synergistic dependencies among the substituents, helped to create a single, statistically significant, model of all fortyone (fortysix) compounds. A fact that was also noted by Hernandez-Gallegos and Lehmann E where crossterms of R1 and R2 replaced the original terms in their final equations [6]. However, they stated that an R2-R3 interdependency made no improvement in the analysis.…”

Section: Discussionmentioning

confidence: 85%

“…In this article the PLS technique is used to derive an improved relationship of Free-Wilson type for the analgesic potency of some N-alkylmorphinan-6-ones previously studied by Hernandez-Gallegos and Lehmann using MLR [6].…”

Section: Introductionmentioning

confidence: 99%

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Multivariate Free‐Wilson Analysis of Some N‐Alkylmorphinan‐6‐one Opioids Using PLS

Norinder¹

1993

Quant. Struct.‐Act. Relat.

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MethodsThe PLS method is used to derive an improved, unified and statistically significant Free;Wilson QSAR model for the analgesic potency of some N-alkylmorphinan-6-one opioids by the inclusion of a large number of first order cross-terms between the substituents.To obtain high potency the R I / R~ substituent-pair should be a cyclo-butyl and a hydrogen (fenol), respectively, while the R3 substituent can be either an oxygen or a methylene bridge.The R4-and R = , substituents can both be a hydrogen or a methyl group to retain high potency of the opioids. Contrary to this, the R I / R~ pairs cyclo-propylhydrogen and cyclo-butyllmethyl as well as a n-propyl substituent in the R5 position are quite unfavorable in this respect. Free-Wilson Description of the StructuresThe FW descriptor matrix consisted of thirteen columns for the R1-R5 substituents (see scheme). An additional sixtysix columns representing all possible first order cross-terms between substituents were also used (i.e. var # 14 = 1*4,15 = 1*5 . . . 24 = 2*4 . . . 79 = 9*13). CHZ-R,I Abbreviations: PLS-Partial least squares projections to latent 0 structures; CoMFA-Comparative molecular field analysis; QSAR-Quantitative structure-activity relationship; MLR-Multiple linear regression; FB-Fujita-Ban modification; FW-Free-Wilson

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 85%

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Multivariate Free‐Wilson Analysis of Some N‐Alkylmorphinan‐6‐one Opioids Using PLS

Norinder¹

1993

Quant. Struct.‐Act. Relat.

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“…The synthesis of aminothiazole 10 began with a Friedel-Crafts acylation of 8-phenyl-1-octanol to produce the acetophenone 17. The alcohol was converted to the azide through the mesylate followed by α-bromination with CuBr 2 to provide 8 18.…”

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confidence: 99%

Potent Ligands for Prokaryotic UDP-Galactopyranose Mutase That Exploit an Enzyme Subsite

Dykhuizen

Kiessling

2008

Org. Lett.

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UDP-Galactopyranose mutase (UGM or Glf), which catalyzes the interconversion of UDPgalactopyranose and UDP-galactofuranose, is implicated in the viability and virulence of multiple pathogenic microorganisms. Here we report the synthesis of high-affinity ligands for UGM homologs from Klebsiella pneumoniae and Mycobacterium tuberculosis. The potency of these compounds stems from their ability to access both the substrate binding pocket and an adjacent site.Galactofuranose (Galf) residues are present in many pathogenic microorganisms. 1 Perhaps the most notorious of these is Mycobacterium tuberculosis, which depends upon Galf residues as essential cell wall components. 2 The biogenesis of Galf-containing glycoconjugates requires the precursor uridine 5′-diphosphogalactofuranose (UDP-Galf). This building block is produced from UDP-galactopyranose (UDP-Galp) by the action of UDP-galactopyranose mutase (UGM) (Figure 1). The gene encoding UGM (glf) is essential for mycobacterial viability, 3 indicating that Galf-containing glycoconjugates are necessary components of the mycobacterial cell wall. Moreover, Galf residues are absent from mammalian glycoconjugates, and UGM inhibitors can block mycobacterial cell growth. 4 These observations underpin the appeal of UGM as a therapeutic target.Most inhibitors of UGM mimic the natural ligand, UDP-Gal. Simple sugar derivatives, including Galp or Galf analogs, can serve as inhibitors, but their activities are relatively modest. 5 Inhibitors that incorporate the uridine portion of the substrate bind substantially better, with affinities that approximate that of UDP-Galp (K d ~ 50 μM). 6,7 Recently, we and others have identified several non substrate-based molecules as ligands. 4,[8][9][10] These Supporting Information Available Detailed experimental procedures, including binding curves and compound synthesis. This information is available free of charge via the internet at http://pubs.acs.org. Our efforts to generate high-affinity UGM ligands were guided by our previous design of a fluorescent UGM ligand. 9 We concluded that the UDP moiety of the substrate contributes the majority of the binding energy, 9 and subsequent studies provide additional support. 6,11 Accordingly, we tethered a fluorophore to UDP through the diphosphoryl group. UDP binds to the UGM from K. pneumoniae (UGM kleb ) with an affinity of 26 μM and to the homolog from M. tuberculosis (UGM myco ) with an affinity of 15 μM; therefore, we expected the UDP-fluorescein probe to bind with an affinity in the same range. In contrast, the probe is a potent ligand, with an affinity approximately 100-fold higher than that of UDP. Specifically, its K d for UGM kleb is 0.10 μM and that for UGM myco is 0.16 μM. The finding that the addition of a fluorescein group enhances affinity suggests that the fluorophore can access a secondary binding site on the enzyme. NIH Public AccessIf the fluorescein moiety occupies an adjacent subsite, the linker separating it and the UDP moiety should influence binding. To test this hyp...

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“…The calculations were made by an FW/FB computer program, which has been used previously in this kind of analysis. 12,13 For the FW/FB analyses, all the 28 compounds were included by supposing that both agonists and antagonists are interacting with the receptor by a similar binding mode. The compound (−)6 was chosen as the reference compound for all the analyses.…”

Section: Free-wilson Methodsmentioning

confidence: 99%

A quantitation of stereoselectivity by the Free-Wilson method

Hernández-Gallegos

Lehmann

1999

Chirality

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A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids

Cited by 11 publications

References 2 publications

Multivariate Free‐Wilson Analysis of Some N‐Alkylmorphinan‐6‐one Opioids Using PLS

Multivariate Free‐Wilson Analysis of Some N‐Alkylmorphinan‐6‐one Opioids Using PLS

Potent Ligands for Prokaryotic UDP-Galactopyranose Mutase That Exploit an Enzyme Subsite

A quantitation of stereoselectivity by the Free-Wilson method

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