Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

Kortagere, Sandhya; Gmeiner, Peter; Weinstein, Harel; Schetz, John A.

doi:10.1124/mol.104.001321

Cited by 38 publications

(70 citation statements)

References 39 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Second, it demonstrates how key molecular interactions between a ligand and a specific GPCR microdomain are influenced by occupancy of an allosteric site. In our case, the interactions that become accessible through the allosteric effect of sodium binding involve a -stack or T-type interaction between the ligand's aryl moiety and F2.61(91) of the receptor as we proposed previously (Kortagere et al, 2004). However, we found that in the D 2 -V2.61(91)F receptor, this favorable interaction can occur only if an interhelical -stack between the F2.61(91) and the adjacent F3.28(110), which forms a "hydrophobic brace," is disrupted.…”

Section: Discussionmentioning

confidence: 91%

“…For all ligands tested within this structure class, the D 2 -V2.61(91)F mutant had affinities very similar to those measured for the wild-type D 2 receptor, including L-745,870 and six other D 4 -selective 1,4-DAPs (1.1-3.3-fold changes, Table 1). All of these 1,4-DAPs have been tested in previous binding studies designed to investigate molecular determinants of ligand selectivity for D 4 receptors versus D 2 receptor subtypes (Schetz et al, 2000;Kortagere et al, 2004), but only one of them (L-745,870 or CPPMA) had been tested on the D 2 -V2.61(91)F mutant, and it was reported to have a large improvement in binding affinity (Simpson et al, 1999).…”

Section: Ligand Docking Into D 2 Receptor Conformers From the M 19mentioning

confidence: 99%

“…Because the amplitude of the M 19 Naϩ trajectory was set arbitrarily in the NMA calculation, we were most interested in the smallest backbone movements away from the initial structure (Ϯ1, 2, 3) rather than the extremes (Ϯ7). Docking of L-745,870 into the various frames of the receptor oscillating along the M 19 Naϩ harmonic motion shows that even a minimal excursion into the open phase of M 19 better accommodates the expected ligand binding poses (see Kortagere et al, 2004) and, hence, facilitates a direct interaction between either of the ligand's aryl moieties and the phenyl ring in the V2.61 (91) frames is because of the increase in the TM2 proline kink bend angle and TM3 lateral translation and increased accessible depth of the binding cleft that is noticeable in Fig. 7A (note the position of the gray regions that depict regions favorable to ligand occupancy).…”

Section: Ligand Docking Guided By Conformations From M 19mentioning

confidence: 99%

“…Cells were then incubated the presence of the drug dilutions at 37°C for 20 min and then centrifuged at 1500g for 5 min. Drug dilutions (Simpson et al, 1999;Schetz et al, 2000;Kortagere et al, 2004;Floresca et al, 2005). Although most ligands bind an orthosteric binding site accessible from the extracellular face of the receptor (Floresca and Schetz, 2004), the sodium ion binds the receptor through an intracellular allosteric binding site formed by the interactions of transmembrane segments 2, 3, and 7 (Neve et al, 2001).…”

Section: ϩmentioning

confidence: 99%

See 3 more Smart Citations

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Ericksen

Cummings

Weinstein

et al. 2008

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

We have uncovered a significant allosteric response of the D 2 dopamine receptor to physiologically relevant concentrations of sodium (140 mM Our findings demonstrate how key interactions can be modulated by occupancy at an allosteric site and are consistent with a mechanism in which sodium binding enhances the affinity of selected ligands through dynamic changes that increase accessibility of substituted benzamides and 1,4-DAP ligands to the orthosteric site and accessibility of 1,4-DAPs to V2.61(91)F.Sodium ions have been shown to modulate dopamine receptors, and allosteric modulation by sodium ions has been shown to drive the conformational equilibrium of heterotrimeric G protein-coupled receptors (GPCRs) toward an agonist low-affinity state (for review, see Schetz, 2005). In dopamine receptors, like in other heterotrimeric GPCRs, the highly conserved and negatively charged aspartic acid at position 2.50 (the generic numbering system is defined in Ballesteros and Weinstein, 1995) has been identified as a sodium interaction site. For example, charge-neutralizing mutations in the D 2 or the D 4 receptor [e.g., D2.50(80)N or D2.50(80)A] make them sodium-insensitive, whereas a charge-sparing mutation [e.g., D2.50(80)E] retains much of the sodium sensitivity (Neve et al

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Ligand Docking Into D 2 Receptor Conformers From the M 19mentioning

confidence: 99%

Section: Ligand Docking Guided By Conformations From M 19mentioning

confidence: 99%

Section: ϩmentioning

confidence: 99%

See 2 more Smart Citations

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Ericksen

Cummings

Weinstein

et al. 2008

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…For both structures, the linker is lined with Phe106, Val107, Tyr365, Thr369, and Thr373, in agreement with mutagenesis data on D3R or other dopamine receptors. 26 Both HM and X-ray structure explained very well the observed structure-activity relationships for D3R ligands. Briefly, an aromatic group is very important in the subcavity occupied by the phenyl of BP897.…”

mentioning

confidence: 72%

Homology Model Versus X-ray Structure in Receptor-based Drug Design: A Retrospective Analysis with the Dopamine D3 Receptor

Levoin

Calmels

Krief

et al. 2011

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly true for G protein-coupled receptors (GPCRs), one of the most important targets for approved medicines and current drug discovery projects. However, very few studies have tested their validity in comparison with corresponding crystal structures, especially in a lead optimization perspective. The recent solving of dopamine D3 receptor crystal structure allowed us to assess our historical homology model. We performed a statistical analysis, by docking our in-house lead optimization library of 1500 molecules. We demonstrate here that the refined homology model suits at least as well as the X-ray structure. It is concluded that when the crystal structure of a given GPCR is not available, homology modeling can be an excellent surrogate to support drug discovery efforts.KEYWORDS: Dopamine D3 receptor, G protein-coupled receptors, docking, homology model, lead optimization S tructure-based design (SBD) uses the information brought by a receptor three-dimensional (3D) model to help the discovery and optimization of ligands. The protein 3D representation gives insights into the shape and electrostatics of the binding site, as well as the nature of its constitutive amino acids. Indeed, it gives insights into the possible interactions that ligands could form. SBD is widely used in medicinal chemistry at different stages of the drug discovery process. In the earliest, SBD can be instrumental in selecting new hits from a large library, thus reducing the size of the compounds to be experimentally tested (hit finding). Many examples in the literature report the success of virtual screening studies.1,2 SBD has also proved very useful in the following step of lead optimization, notably as a tool to understand and rationalize the structure-activity relationships. 3This approach commonly starts from a reliable crystal structure of the target receptor. However, in comparison with the huge number of proteins of pharmaceutical interest, the number of available crystal structures is limited. This is particularly true for G protein-coupled receptors (GPCRs), the most important class of drug targets whose ligands represent about 50% of the currently marketed drugs. 4 To compensate for the scarcity of crystal structures, molecular models of target proteins are often built based on a close structural neighbor (comparative/homology modeling). For GPCRs, bovine rhodopsin has long been the sole experimental structure available. So, a myriad of homology models (HMs) deriving from the breakthrough of Palczewski's work 5 were built and used in virtual screening experiments.

show abstract

Dopaminergic Neurotransmission

Schetz

Sibley

2007

Handbook of Contemporary Neuropharmacology

View full text Add to dashboard Cite

Dopamine is a neurotransmitter in the central and peripheral nervous systems where it regulates numerous physiological processes. Within the CNS, dopamine is known to regulate emotion, reward, cognition, memory, endocrine functions, and motor control. Alterations in dopaminergic transmission are known to be involved in the etiology and/or therapy of a number of neurological and psychiatric disorders including Parkinson's disease, Tourette's syndrome, attention deficit hyperactivity disorder, schizophrenia and substance use. One of the hallmarks of these disorders is that they are all treated with drugs that either enhance or impede dopaminergic transmission. Dopamine exerts its effects by binding to and activating five different receptor proteins that are members of the G protein‐coupled receptor (GPCR) family. These five receptors are made up of two subfamilies: D 1 ‐like D 2 ‐like. The D 1 and D 5 receptors comprise the D 1 ‐like subfamily while the D 2 , D 3 and D 4 receptors make up the D 2 ‐like subfamily. In general, the D 1 ‐like receptors stimulate the production of the ubiquitous second messenger cAMP whereas D 2 ‐like receptors suppress cAMP production and also couple to additional signaling pathways. Different therapeutic agents are known to selectively activate or inhibit each of the dopamine receptor subtypes. A current goal of medicinal chemists is to develop drugs with even greater selectivity or specific mixed properties for the treatment of brain disorders that are associated with aberrations in various dopaminergic signaling pathways.

show abstract

Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

Cited by 38 publications

References 39 publications

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Homology Model Versus X-ray Structure in Receptor-based Drug Design: A Retrospective Analysis with the Dopamine D3 Receptor

Dopaminergic Neurotransmission

Contact Info

Product

Resources

About

Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

Cited by 38 publications

References 39 publications

Ligand Selectivity of D2Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Ligand Selectivity of D2Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Homology Model Versus X-ray Structure in Receptor-based Drug Design: A Retrospective Analysis with the Dopamine D3 Receptor

Dopaminergic Neurotransmission

Contact Info

Product

Resources

About

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding

Ligand Selectivity of D₂Dopamine Receptors Is Modulated by Changes in Local Dynamics Produced by Sodium Binding