Mutual Cooperativity of Three Allosteric Sites on the Dopamine D1 Receptor.
Journal
Molecular pharmacology
ISSN: 1521-0111
Titre abrégé: Mol Pharmacol
Pays: United States
ID NLM: 0035623
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
05
08
2022
accepted:
01
12
2022
entrez:
21
2
2023
pubmed:
22
2
2023
medline:
25
2
2023
Statut:
ppublish
Résumé
An amine-containing molecule called Compound A has been reported by a group from Bristol-Myers Squibb to act as a positive allosteric modulator (PAM) at the dopamine D1 receptor. We synthesized the more active enantiomer of Compound A (BMS-A1) and compared it with the D1 PAMs DETQ and MLS6585, which are known to bind to intracellular loop 2 and the extracellular portion of transmembrane helix 7, respectively. Results from D1/D5 chimeras indicated that PAM activity of BMS-A1 tracked with the presence of D1 sequence in the N-terminal/extracellular region of the D1 receptor, a unique location compared with either of the other PAMs. In pairwise combinations, BMS-A1 potentiated the small allo-agonist activity of each of the other PAMs, while the triple PAM combination (in the absence of dopamine) produced a cAMP response about 64% of the maximum produced by dopamine. Each of the pairwise PAM combinations produced a much larger leftward shift of the dopamine EC
Identifiants
pubmed: 36804203
pii: molpharm.122.000605
doi: 10.1124/molpharm.122.000605
doi:
Substances chimiques
Dopamine
VTD58H1Z2X
Receptors, Dopamine D1
0
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
176-187Informations de copyright
Copyright © 2023 by The Author(s).