Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D3 Receptor-Selective Agonist (4aR,10bR)-(+)-trans-3,4,4a,10b- Tetrahydro-4-n-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907)

Vliet, LA van; Rodenhuis, Nienke; Dijkstra, Durk; Wikström, Håkan; Ta, Pugsley; Serpa, K.A.; Meltzer, Leonard T.; Heffner, Thomas G.; Wise, Lawrence D.; Lajiness, ME; Rm, Huff; Svensson, Kjell; Sundell, Staffan; Lundmark, M.

doi:10.1021/jm0000113

Cited by 142 publications

(61 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We find, however, that our current striatal clozapine D2 occupancy (80 ± 7%) is very similar to that of our earlier report (80 ± 8%) in which a twofold lower injected [ 3 H]-( + )-PHNO dose was used (McCormick et al, 2008). [ 3 H]-( + )-PHNO has been reported to have 30-to 45-fold higher in vitro affinity for the D3 receptor than the D2 receptor (Freedman et al, 1994;van Vliet et al, 2000) suggesting that a lower injected dose may be required to fulfill tracer dose conditions for D3 compared with D2. In the absence of reports comparing the in vivo affinity of [ 3 H]-( + )-PHNO, it remains possible that the tracer dose range has been exceeded with respect to the D3 receptor, consequently presenting the possibility of underestimated drug D3 receptor occupancy.…”

Section: Discussionsupporting

confidence: 91%

“…In agreement with its high in vitro affinity for both D2 and D3 receptors (Freedman et al, 1994;van Vliet et al, 2000), the agonist positron emission tomography (PET) radiotracer [ 11 C]-( + )-PHNO is thought to label both receptor subtypes in vivo. In both human and baboon, the regional pattern of in vivo [ 11 C]-( + )-PHNO binding is unique among D2/D3 radiotracers, with highest binding in the globus pallidus (GP) followed by ventral striatum (VS), caudate (CAU) and putamen (PUT), and substantia nigra (SN) (Ginovart et al, 2007;Narendran et al, 2006;Willeit et al, 2006).…”

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

McCormick

Kapur

Graff‐Guerrero

et al. 2010

Neuropsychopharmacol

View full text Add to dashboard Cite

In a recent human [ 11 C]-( + )-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [ 3 H]-( + )-PHNO binding sites in rat brain and (2) to compare, using [ 3 H]-( + )-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [ 3 H]-( + )-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [ 3 H]-( + )-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying B80% D2, did not occupy D3 receptors. Clozapine, which also occupied B80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [ 3 H]-( + )-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 91%

The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

McCormick

Kapur

Graff‐Guerrero

et al. 2010

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…24,26 Sumanirole also has a 250-fold selectivity for D2 over D3 receptors, 26 but the affinity of PD-128907 for D 3 R is only 15 to 30 times higher than that for D2R in rats. 23 Thus, sumanirole is unlikely to interact efficiently with D3R at relevant pharmacological concentrations, but PD-128907, depending on the dose used, may act as a D3R or a D2/D3R agonist. 25,26,30 Pharmacological and genetic studies have provided strong evidence that two very characteristic effects of DA agonists, hypothermia and yawning, are mediated by D2R and D3R respectively.…”

Section: Discussionmentioning

confidence: 99%

“…19, 20, 21 In the present study, we therefore set out to determine the respective contributions of these DA receptors in the reversal of the motivational and affective impairments induced by SNc DA neuronal loss. Using DA agonists selective for D 1 R (SKF-38393), D 2 R (sumanirole) or preferential for D3R (PD-128907), 22, 23, 24, 25, 26 we showed that all DA agonists corrected the affective impairments, but only the preferential D3R agonist reversed the motivational deficits induced by the SNc DA lesions, providing a potential specific target for the treatment of PD-related neuropsychiatric symptoms.…”

Section: Introductionmentioning

confidence: 96%

Implication of dopamine D3 receptor activation in the reversion of Parkinson’s disease-related motivational deficits

et al. 2014

View full text Add to dashboard Cite

In addition to the classical motor symptoms, motivational and affective deficits are core impairments of Parkinson's disease (PD). We recently demonstrated, by lesional approaches in rats, that degeneration of the substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is likely to have a crucial role in the development of these neuropsychiatry symptoms. We have also shown that, as in clinical investigations, chronic treatment with levodopa or the DA D2/D3 receptor (D2/D3R) agonist ropinirole specifically reverses these PD-related motivational deficits. The roles of specific DA receptor subtypes in such reversal effects remain, however, unknown. We therefore investigated here the precise involvement of D1, D2 and D3R in the reversal of the motivational and affective deficits related to SNc DA neuronal loss. Three weeks after bilateral and partial 6-hydroxydopamine (6-OHDA) SNc lesions, rats received 14 daily intraperitoneal administrations of the selective D1R agonist SKF-38393 (2.5 or 3.5 mg kg−1), the selective D2R agonist sumanirole (0.1 or 0.15 mg kg−1), or the preferring D3R gonist PD-128907 (0.1 or 0.15 mg kg−1). Anxiety-, depressive-like and motivated behaviors were assessed in an elevated-plus maze, a forced-swim test, and an operant sucrose self-administration procedure, respectively. All DA agonists attenuated anxiety- and depressive-like behaviors. However, only PD-128907 reversed the motivational deficits induced by 6-OHDA SNc lesions. This effect was blocked by a selective D3R (SB-277011A, 10 mg kg−1), but not D2R (L-741,626, 1.5 mg kg−1), antagonist. These data provide strong evidence for the role of D3R in motivational processes and identify this receptor as a potentially valuable target for the treatment of PD-related neuropsychiatric symptoms.

show abstract

“…Bioisosterism is a concept that continues to be widely applied in medicinal chemistry to make informed modifications to potential new drug compounds [1][2][3][4][5][6][7][8]. These modifications make it possible to alter key properties such as solubility or toxicity while the activity of a molecule is enhanced or maintained.…”

Section: Introductionmentioning

confidence: 99%

In Silico Techniques for the Identification of Bioisosteric Replacements for Drug Design

Devereux¹,

Popelier²

2010

CTMC

View full text Add to dashboard Cite

This article provides an overview of the broad and increasingly varied selection of computational approaches available to find bioisosteric replacements for fragments of bioactive compounds. The rapidly increasing number and diversity of methods has provided medicinal chemists with a powerful range of commercial and academic tools to aid in the optimization of lead compound activity and ADMET properties for drug design. We discuss methods with fundamentally different philosophies, ranging from evaluation of similarity in a calculated property space to cheminformatics analysis of pharmaceutical compound databases. We also discuss the incorporation, within these methods, of a whole spectrum of experimental and calculated data to describe fragment chemistry and compound activity. Despite the growing sophistication of available techniques, there remains much scope for further development and especially for deeper validation of the efficacy of different approaches in what seems set to remain an expanding field.

show abstract

Synthesis and Pharmacological Evaluation of Thiopyran Analogues of the Dopamine D₃ Receptor-Selective Agonist (4aR,10bR)-(+)-trans-3,4,4a,10b- Tetrahydro-4-n-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol (PD 128907)

Cited by 142 publications

References 49 publications

The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

Implication of dopamine D3 receptor activation in the reversion of Parkinson’s disease-related motivational deficits

In Silico Techniques for the Identification of Bioisosteric Replacements for Drug Design

Contact Info

Product

Resources

About