Ligand with Two Modes of Interaction with the Dopamine D-2 Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism [Elektronisk resurs]
-
Ågren, Richard (författare)
-
Zeberg, Hugo (författare)
-
Stępniewski, Tomasz Maciej (författare)
-
Free, R. Benjamin (författare)
-
Reilly, Sean W. (författare)
-
Luedtke, Robert R. (författare)
-
Arhem, Peter (författare)
-
Ciruela, Francisco (författare)
-
Sibley, David R. (författare)
-
Mach, Robert H. (författare)
-
Selent, Jana (författare)
-
Nilsson, Johanna (författare)
-
Sahlholm, Kristoffer (författare)
-
Umeå universitet Medicinska fakulteten (utgivare)
-
Umeå universitet Medicinska fakulteten (utgivare)
- Publicerad: American Chemical Society (ACS), 2020
- Engelska.
-
Ingår i: ACS Chemical Neuroscience. - 1948-7193. ; 11:19, 3130-3143
-
Läs hela texten
-
Läs hela texten
-
Läs hela texten
- Relaterad länk:
-
http://www.umu.se/ (Värdpublikation)
Sammanfattning
Ämnesord
Stäng
- A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D 2 receptor (D 2 R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D 2 R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D 2 R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D 2 R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments.
Ämnesord
- Medical and Health Sciences (hsv)
- Basic Medicine (hsv)
- Neurosciences (hsv)
- Medicin och hälsovetenskap (hsv)
- Medicinska och farmaceutiska grundvetenskaper (hsv)
- Neurovetenskaper (hsv)
Genre
- government publication (marcgt)
Indexterm och SAB-rubrik
- drug kinetics
- competitive binding
- antipsychotics
- PET scan
- molecular dynamics simulation
- Xenopus oocytes
- arrestin
- HEK cells
Inställningar
Hjälp
Ingår i annan publikation. Gå till titeln
ACS Chemical Neuroscience