Dopamine D1/D5 Receptor Antagonists with Improved Pharmacokinetics
Dopamine D1/D5 Receptor Antagonists with Improved Pharmacokinetics: Design, Synthesis, and Biological Evaluation of Phenol Bioisosteric Analogues of Benzazepine D1/D5 Antagonists Wen-Lian Wu , Duane A. Burnett , Richard Spring , William J. Greenlee , Michelle Smith , Leonard Favreau , Ahmad Fawzi , Hongtao Zhang , and Jean E. Lachowicz
Dopamine D1/D5 receptor antagonists with improved
Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity.
The Dopamine D5 receptor contributes to activation of
Interestingly, the D5 receptor is expressed in 88% of cholinergic interneurons (CINs) while only 17% of them express the D1 receptor and none express D3 or D4 receptor 13,14. Furthermore, CINs
The Signaling and Pharmacology of the Dopamine D1 Receptor
The emergence of new non-catechol D1R agonists, biased agonists, and allosteric modulators has renewed clinical interest in drugs targeting this receptor, specifically for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment in neuropsychiatric disorders.
Less is more: pathophysiology of dopaminergic-therapy-related
Application of a D1 or D5 receptor agonist also induced long-term potentiation of C-fibre evoked field potentials in the spinal dorsal horn lasting for more than 10 h. This effect was blocked by the D1 or D5 antagonist SCH23390, whereas the D2 receptor agonist quinpirole reduced C-fibre responses that lasted for 2 h.
- Is halobenzazepine a dopamine receptor antagonist?
- James.bourne@med.monash.edu.au SCH 23390, the halobenzazepine (R)- (+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine, is a highly potent and selective dopamine D1-like receptor antagonist with a K (i) of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes, respectively.
- Are d1/d5r agonists clinically viable?
- These findings, obtained with two pharmacologically divergent D1 agonists, strongly suggest that in order to be clinically viable, D1/D5R agonists designed to treat cognitive impairment will need to avoid over-stimulating D1/D5R signaling.
- Is a68930 a potent agonist for the dopamine D1 receptor?
- A68930: a potent agonist specific for the dopamine D1 receptor. Neurochem. Int. 20 (Suppl.), 157S−160S. 10.1016/0197-0186 (92)90230-o [DOI] [PubMed] [Google Scholar]
- Can drugs directly target the dopamine D1 receptor (D1R)?
- More specifically, drugs that directly target the dopamine D1 receptor (D1R) have been investigated for the treatment of motor impairment in Parkinson's Disease, and cognitive impairment associated with age, neuropsychiatric, and neurodegenerative diseases.
- Is SCH 23390 a d1/d5r antagonist?
- However, a limitation of these studies is that they all used intracerebral injection of the D1/D5R antagonist SCH 23390, a drug which also possesses activity at 5-HT2 receptors (Hyttel, 1983; Briggs et al., 1991).
- Is SCH 23390 the first selective dopamine D1-like receptor antagonist?
- Bourne JA. SCH 23390: the first selective dopamine D1-like receptor antagonist. CNS Drug Rev. 2001;7:399–414. Waddington JL, O’Boyle KM. Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D1 antagonist. Pharmacol Ther. 1989;43:1–52. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS.
