Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.
Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D(2) receptor (D(2)R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D(2)R agonists that display signaling bias via β-arrestin-ergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin-biased D(2)R ligands. These compounds also represent unprecedented β-arrestin-biased ligands for a G(i)-coupled G protein-coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G(i)-regulated cAMP production and partial agonists for D(2)R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin-biased D(2)R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin-biased D(2)R ligands represent valuable chemical probes for further investigations of D(2)R signaling in health and disease.
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
John A
JA
Allen
Julianne M
JM
Yost
Vincent
V
Setola
Xin
X
Chen
Maria F
MF
Sassano
Meng
M
Chen
Sean
S
Peterson
Prem N
PN
Yadav
Xi-ping
XP
Huang
Bo
B
Feng
Niels H
NH
Jensen
Xin
X
Che
Xu
X
Bai
Stephen V
SV
Frye
William C
WC
Wetsel
Marc G
MG
Caron
Jonathan A
JA
Javitch
Bryan L
BL
Roth
Jian
J
Jin
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D018491:Dopamine Agonists / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D014150:Antipsychotic Agents; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D018491:Dopamine Agonists; D008024:Ligands; D017448:Receptors, Dopamine D2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP