Dopamine receptor model and its application in the design of a new class of rigid pyrrolo[2,3-g]isoquinoline antipsychotics

Olson, Gary L.; Cheung, H.‐C.; Morgan, Keith D.; Blount, John F.; Todaro, Louis J.; Berger, Léo; Davidson, Arnold B.; Boff, Edward

doi:10.1021/jm00141a002

Cited by 89 publications

(27 citation statements)

References 3 publications

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“…Ligand conformations were either from crystal structures of the ligands or from ab initio calculations. The crystal structures of piquindone (Olson et al, 1981), spiperone (Liang et al, 1998), and haloperidol (Reed and Schaefer, 1973) were described previously. For tropapride, eight conformations were generated from the degrees of freedom and subjected to ab initio quantum mechanical calculations using the basis sets 3-21G* and 6-31G* in the program Spartan (Wavefunction, Inc., Irvine, CA), producing minimized conformations of approximately equal energy.…”

Section: Materials [mentioning

confidence: 99%

Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors

et al. 2005

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To test the hypothesis that pharmacological differentiation between D 1 and D 2 dopamine receptors results from interactions of selective ligands with nonconserved residues lining the binding pocket, we mutated amino acid residues in the D 2 receptor to the corresponding aligned residues in the D 1 receptor and vice versa and expressed the receptors in human embryonic kidney 293 cells. Determinations of the affinity of the 14 mutant D 2 receptors and 11 mutant D 1 receptors for D 1 -and D 2 -selective antagonists, and rhodopsin-based homology models of the two receptors, identified two residues whose direct interactions with certain ligands probably contribute to ligand selectivity. The D 1 receptor mutant W99 3.28 F showed dramatically increased affinity for several D 2 -selective antagonists, particularly spiperone (225-fold), whereas the D 2 receptor mutant Y417 7.43 W had greatly decreased affinity for benzamide ligands such as raclopride (200-fold) and sulpiride (125-fold).The binding of the,5-tetrahydro-1H-3-benzazepine (SCH23390) was unaffected, indicating that SCH23390 makes little contact with these ancillary pocket residues. Mutation of A/V 5.39 caused modest but consistent and reciprocal changes in affinity of the receptors for D 1 and D 2 -selective ligands, perhaps reflecting altered packing of the interface of helices 5 and 6. We also obtained some evidence that residues in the second extracellular loop contribute to ligand binding. We conclude that additional determinants of D 1 /D 2 receptorselective binding are located either in that loop or in the transmembrane helices but, like residue 5.39, indirectly influence the interactions of selective ligands with conserved residues by altering the shape of the primary and ancillary binding pockets. Dopamine modulates diverse biological functions, including movement, endocrine function, and memory formation, through activation of five distinct dopamine receptor subtypes that belong to the G protein-coupled receptor (GPCR) superfamily and are grouped into two subfamilies, D 1 -like dopamine receptors and D 2 -like dopamine receptors, based on their structure, pharmacology, and transduction pathways. The D 1 and D 2 receptors are the most abundant dopamine receptor subtypes and are most similar to the traditional pharmacologically defined D 1 and D 2 receptors (Kebabian and Calne, 1979). The D 1 receptor has a long carboxyl terminus and a short third intracellular loop, couples to the adenylate cyclase stimulatory G proteins G␣ s/olf , and stimulates cyclic AMP accumulation. In contrast, the D 2 receptor has a short carboxyl terminus and a long third intracellular loop, couples to the pertussis toxin-sensitive G proteins G␣ i/o , inhibits cyclic AMP accumulation, and also modulates a variety of G␤␥-regulated effectors such as calcium and potassium ion channels, mitogen-activated protein kinases, and phospholipases (Neve et al., 2004). D 1 and D 2 receptor-selective agonists and antagonists are current or potential therapeutic drugs for treatment o...

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Section: Materials [mentioning

confidence: 99%

Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors

et al. 2005

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“…The common characteristic of carbonyl oxygen and an aromatic ring is their electron density localization. This indicates the pharmacophoric equivalence of the two groups [28].…”

Section: Extension To Other Antipsychotic Compoundsmentioning

confidence: 76%

Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

Atlamazoglou

Thireou

Eliopoulos

2007

J Comput Aided Mol Des

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The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implemented for dopamine antagonists of the D(2) receptor subtype. The molecular structures of the antagonists included in this analysis were categorized into two structurally distinct classes. Using structural superposition with internal energy minimization, two pharmacophore models were deduced. Based on these two models other D(2) antagonists that fulfil them were derived and studied. This procedure aided the identification of the common 3D patterns present in diverse molecules that act at the same biological target and the extraction of a common molecular framework for the two structural classes. The pharmacophoric information was found to be suitable for guiding superposition of structurally diverse molecules, using a more biologically meaningful selection of the targeting points.

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“…While the sum of the bond angles about N(2) ~ is quite similar, the endocyclic angle C (1) (7) 94 ( actions are absent, such as molindone (Olson, Cheung, Morgan, Blount, Todaro, Berger, Davidson & Boff, 1981), moxnidazole (Goldberg, 1982)or moclobemide (Durant, Van der Brempt, Bufkens & Evrard, 1986). The pharmacological inactivity of the title compound is possibly related to some of the structural modifications introduced by the epoxyethano bridge.…”

Section: C(13b)-h(13ab)o(14a")mentioning

confidence: 96%

Structure of a κ-opioid receptor misfit: (1S,5R,8R,9R)-2'-hydroxy-5,9-dimethyl-8,2-epoxyethano-6,7-benzomorphan hydrochloride

et al. 1989

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Dopamine receptor model and its application in the design of a new class of rigid pyrrolo[2,3-g]isoquinoline antipsychotics

Cited by 89 publications

References 3 publications

Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors

Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors

Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

Structure of a κ-opioid receptor misfit: (1S,5R,8R,9R)-2'-hydroxy-5,9-dimethyl-8,2-epoxyethano-6,7-benzomorphan hydrochloride

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Dopamine receptor model and its application in the design of a new class of rigid pyrrolo[2,3-g]isoquinoline antipsychotics

Cited by 89 publications

References 3 publications

Structural Determinants of Pharmacological Specificity Between D1and D2Dopamine Receptors

Structural Determinants of Pharmacological Specificity Between D1and D2Dopamine Receptors

Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

Structure of a κ-opioid receptor misfit: (1S,5R,8R,9R)-2'-hydroxy-5,9-dimethyl-8,2-epoxyethano-6,7-benzomorphan hydrochloride

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Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors

Structural Determinants of Pharmacological Specificity Between D₁and D₂Dopamine Receptors