Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route

Blagg, Julian; Allerton, Charlotte; Batchelor, David V.; Baxter, Anthony D.; Burring, Denise J.; Carr, Christopher L.; Cook, Andrew S.; Nichols, Carly L.; Phipps, J. Bradley; Sanderson, Vivienne; Verrier, Hugh; Wong, Sharon

doi:10.1016/j.bmcl.2007.10.059

Cited by 16 publications

(7 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This high degree of selectivity corresponds to PF-592,379 being at least 235-times more D 3 -selective than 7-OH-DPAT (current data), and at least 16-times more D 3 -selective than pramipexole (Blagg et al, 2007), both of which have been shown to substitute for cocaine in drug self-administration and discrimination assays in rats (Acri et al, 1995; Caine and Koob, 1993; Collins et al, 2012; Filip and Przegalinski, 1997). Given the high levels of predictive validity that are provided by these two assays (for recent reviews see; Carter and Griffiths, 2009; O'Connor et al, 2011), the inability of PF-592,379 to maintain self-administration or substituted for the interoceptive effects of cocaine strongly suggests that highly selective D 3 agonists, such as PF-592,379, will have a low potential for abuse.…”

Section: Discussionmentioning

confidence: 61%

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

Collins¹,

Butler²,

Wayman³

et al. 2012

Behavioural Pharmacology

View full text Add to dashboard Cite

Dopamine D3-preferring agonists are commonly used to treat Parkinson’s disease and restless leg syndrome; however, laboratory animal studies suggest that they may possess a moderate abuse potential. These studies aimed to compare the highly-selective, full D3 agonist PF-592,379 to that of the less selective D3 agonist 7-OH-DPAT, and the indirect dopamine agonist cocaine in drug self-administration and discrimination assays. Although rats readily acquired high rates of fixed ratio (FR)1 responding for cocaine, experimentally naïve rats failed to acquire responding when 7-OH-DPAT or PF-592,379 were made available during an 18-session acquisition period. Cocaine also maintained dose-dependent levels of responding when available under an FR5 or progressive ratio (PR) schedule of reinforcement. Although, 7-OH-DPAT maintained modest levels responding when substituted under an FR5, it failed to maintain significant levels of PR responding. PF-592,379 maintained saline-like rates of responding when substituted under FR5 or PR schedules of reinforcement. Similar behavioral profiles were observed in cocaine discrimination assays, with 7-OH-DPAT partially substituting for cocaine, and PF-592,379 producing saline-like effects over a wide range of doses. Together, the results of these studies predict that highly selective D3 agonists, such as PF-592,379, will have low abuse potential in humans.

show abstract

Section: Discussionmentioning

confidence: 61%

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

Collins¹,

Butler²,

Wayman³

et al. 2012

Behavioural Pharmacology

View full text Add to dashboard Cite

show abstract

“…The cyclization step usually involves a substituted 1,2‐amino alcohol undergoing either a base mediated S N 2 reaction or a transition metal‐mediated allylic substitution. Examples of representantive morpholine ring formations are presented in Figure …”

Section: Medicinal Chemistry Of Morpholine Derivativesmentioning

confidence: 99%

“…Conditions: (a) chloroacetyl chloride, NaOH, H 2 O, DCM, rt, 30 minutes, then aq. KOH, IPA, rt, 2 hours (yield: 90%); (b) BH 3 ·THF, reflux, 3 hours (yield: 93%); (c) DEAD, Ph 3 P, toluene (yield: 92%); (d) acetone, rt (yield: 67%)…”

Section: Medicinal Chemistry Of Morpholine Derivativesmentioning

confidence: 99%

“…Although dual D 2 and D 3 receptor agonists, such as apomorphine, were used for the treatment of male erectile dysfunction, they were proven to be possessing dose‐limiting side effects due to their D 2 agonism. Based on that, a Pfizer drug discovery project, set to develop a selective D 3 agonist, resulted in the agonist 96 which has a D 3 EC 50 = 8 nM and a D 2 EC 50 > 10 μM (Figure ) . The aryl morpholine core structure of 96 was the outcome of a small scale HTS whereas SAR studies were conducted to improve affinity and selectivity for D 3 .…”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

See 1 more Smart Citation

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

187

114

View full text Add to dashboard Cite

Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

show abstract

“…[12] Another deprotected product 3l bearing an electron-donating 3-methoxy substituent can be further converted to a dopamine 3 receptor agonist 4l via reductive amination to 3l' in 75% yield and 88% ee and further demethylation (Figure 3c). [13] A deuterium-labelling experiment was also conducted to reveal the mechanism of this reaction (Figure 4). When H2 was replaced by D2, two deuterium atoms were substituted to both of the adjacent carbons, which indicates that the hydrogenation only occurs at the C=C bond of the enamide stage.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric hydrogenation for the synthesis of 2-substituted chiral morpholines

Zhang

Zou

et al. 2021

Chem. Sci.

View full text Add to dashboard Cite

show abstract

Design and synthesis of a functionally selective D3 agonist and its in vivo delivery via the intranasal route

Cited by 16 publications

References 13 publications

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

Lack of abuse potential in a highly selective dopamine D3 agonist, PF-592,379, in drug self-administration and drug discrimination in rats

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Asymmetric hydrogenation for the synthesis of 2-substituted chiral morpholines

Contact Info

Product

Resources

About