A study of the structure–activity relationship of GABAA–benzodiazepine receptor bivalent ligands by conformational analysis with low temperature NMR and X-ray analysis

Han, Daxiong; Försterling, F. Holger; Li, Xiaoyan; Deschamps, Jeffrey R.; Parrish, Damon A.; Cao, Helin; Rallapalli, Sundari; Clayton, Terry; Teng, Yun; Majumder, Samarpan; Sankar, S.; Roth, Bryan L.; Sieghart, Werner; Furtmüller, Roman; Rowlett, James K.; Weed, Michael R.; Cook, James M.

doi:10.1016/j.bmc.2008.08.072

Cited by 7 publications

(17 citation statements)

References 43 publications

(38 reference statements)

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“…Bivalent ligands have a preferred linker of 3–5 methylene units, between the two pharmacophores (see XLi-093). This was established by NMR experiments run at low temperatures, X-ray crystallography, and molecular modeling of the ligands in question and will be discussed [ 14 , 17 , 18 ].…”

Section: Subtype Selective Ligands For α 5 mentioning

confidence: 99%

“…Möhler has proposed that α 5 selective inverse agonists or α 5 selective agonists might enhance cognition [ 5 , 13 , 16 – 18 , 86 ]. This is because of the extrasynaptic pyramidal nature of α 5 β 3 γ 2 subtypes, located almost exclusively in the hippocampus.…”

Section: Subtype Selective Agonists For α 5mentioning

confidence: 99%

“…Because of this, a new “potential agonist” which binds solely to α 5 β 3 γ 2 subtypes was designed by computer modeling (see Figure 17 ). This ligand (DM-I-81, 9 ) has an agonist framework and binds only to α 5 β 3 γ 2 subtypes [ 13 , 17 , 18 , 86 ]. The binding potency at α 5 subtypes is 176 nM.…”

Section: Subtype Selective Agonists For α 5mentioning

confidence: 99%

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A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

Clayton

Rallapalli

Biawat

et al. 2015

International Journal of Medicinal Chemistry

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An updated model of the GABA(A) benzodiazepine receptor pharmacophore of the α5-BzR/GABA(A) subtype has been constructed prompted by the synthesis of subtype selective ligands in light of the recent developments in both ligand synthesis, behavioral studies, and molecular modeling studies of the binding site itself. A number of BzR/GABA(A) α5 subtype selective compounds were synthesized, notably α5-subtype selective inverse agonist PWZ-029 (1) which is active in enhancing cognition in both rodents and primates. In addition, a chiral positive allosteric modulator (PAM), SH-053-2′F-R-CH3 (2), has been shown to reverse the deleterious effects in the MAM-model of schizophrenia as well as alleviate constriction in airway smooth muscle. Presented here is an updated model of the pharmacophore for α5β2γ2 Bz/GABA(A) receptors, including a rendering of PWZ-029 docked within the α5-binding pocket showing specific interactions of the molecule with the receptor. Differences in the included volume as compared to α1β2γ2, α2β2γ2, and α3β2γ2 will be illustrated for clarity. These new models enhance the ability to understand structural characteristics of ligands which act as agonists, antagonists, or inverse agonists at the Bz BS of GABA(A) receptors.

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Section: Subtype Selective Ligands For α 5 mentioning

confidence: 99%

Section: Subtype Selective Agonists For α 5mentioning

confidence: 99%

Section: Subtype Selective Agonists For α 5mentioning

confidence: 99%

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A Review of the Updated Pharmacophore for the Alpha 5 GABA(A) Benzodiazepine Receptor Model

Clayton

Rallapalli

Biawat

et al. 2015

International Journal of Medicinal Chemistry

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“…It is interesting to note the use of polybutylene glycol spacer groups,73 which have been designed to counter the natural coil‐like conformation obtained when using PEG spacers,74–76 whilst retaining an element of hydrophilicity and flexibility. On the other hand, multiple oligoproline residues ( 24 ) have been used to form well‐defined helical structures77 for the synthesis of specifically oriented bivalent ligands with a coiled spacer 69.…”

Section: General Features Of Bivalent Ligandsmentioning

confidence: 99%

Design Strategies for Bivalent Ligands Targeting GPCRs

Shonberg¹,

Scammells²,

Capuano³

2011

ChemMedChem

127

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Specifically designed bivalent ligands targeting G protein-coupled receptor (GPCR) dimeric structures have become increasingly popular in recent literature. The advantages of the bivalent approach are numerous, including enhanced potency and receptor subtype specificity. However, the use of bivalent ligands as potential pharmacotherapeutics is limited by problematic molecular properties, such as high molecular weight and lipophilicity. This minireview focuses on the design of bivalent ligands recently described in the literature; discussing the choice of lead pharmacophore, the position and nature of the attachment point for linking the two pharmacophore units, and the length and composition of the spacer group. Furthermore, this minireview distils the molecular descriptors of the bivalent ligands that exhibit in vivo activity, as well as highlights their ability to access the central nervous system.

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“…Among the drugs/compounds used in this patent were the a-5 inverse agonists PWZ029 [65] and XLi356 ( Figure 2) [66]. From a full panel of receptor binding was observed that XLi356 does not bind to other types of receptors and, with PWZ029, were found to reverse scopolamine-induced memory deficit (1 mg/kg) in mice at the dose of 10 mg/kg.…”

Section: Known Compoundsmentioning

confidence: 99%