Molecular modeling of σ1 receptor ligands: a model of binding conformational and electrostatic considerations

Gund, Tamara; Floyd, Jie; Jung, Dawoon

doi:10.1016/j.jmgm.2003.08.001

Cited by 36 publications

(29 citation statements)

References 50 publications

(63 reference statements)

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“…The overall pharmacophores are the triangles including nitrogen, the center of the phenyl ring, and the lone pair of electrons. These are in agreement with our previous 1 receptor ligands pharmacophore 33 ( Fig. 5b) and in close agreement with our first published pharmacophore 34 (Fig.…”

Section: Pharmacophore Informationsupporting

confidence: 94%

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

2004

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Abstract:The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a threedimensional quantitative structure activity relationship (3D-QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma-1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3-21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3-21G*, and ab initio HF/3-21G*, MP2/3-21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3-21G method were better than those from AM1. The best CoMFA was obtained from HF/3-21G* optimized geometry and charges (R 2 ϭ 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3-21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R 2 (0.989 -0.977) from HF/3-21G* optimized geometries than R 2 (0.966 -0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3-21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges.

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Section: Pharmacophore Informationsupporting

confidence: 94%

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

2004

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“…42 Based on this hypothesis Manallack et al and Gund et al superimposed independently different r ligands and defined a distance between the phenyl ring and the basic amino moiety of 5.06 Å (Manallack) and 5.3-5.7 Å (Gund), respectively. [43][44][45] In 1992 Gilligan et al published a r pharmacophore model, which defines the orientation and distances of two 'hydrophobic groups' and one 'basic nitrogen center' to each other for potent r 1 ligands. 46 (Fig.…”

Section: Pharmacophore Models Of R 1 Ligandsmentioning

confidence: 99%

Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

Rack¹,

Fröhlich²,

Schepmann³

et al. 2011

Bioorganic & Medicinal Chemistry

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“…Gund et al (2004) employed the PD144418 structure in molecular modeling work to help establish a s 1 receptor pharmacophore. Navarro and coworkers (2010) used the ligand in vitro during their characterization of functional heteromers of s 1 and dopamine D 1 receptors.…”

Section: Introductionmentioning

confidence: 99%

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Lever

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (s 1 ) receptors. Selective s 1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity s 1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated s 1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for s 1 sites (K i 0.46 nM) and 3596-fold selectivity over s 2 sites (K i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (K i .100 mM), and the DAT interaction was weak (K i 9.0 mM). In vivo, PD144418 bound to central and peripheral s 1 sites in mouse, with an ED 50 of 0.22 mmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 mmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 mmol/kg) attenuated cocaine-induced hyperactivity in a dosedependent manner in mice. There was good correlation (r 2 5 0.88) of hyperactivity reduction with increasing cerebral s 1 receptor occupancy. The behavioral ED 50 of 0.79 mmol/kg corresponded to 80% occupancy. Significant s 1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 mmol/kg dose of PD144418.

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Molecular modeling of σ1 receptor ligands: a model of binding conformational and electrostatic considerations

Cited by 36 publications

References 50 publications

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

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