Abstract
There is ongoing debate about the role of G protein–coupled receptor kinases (GRKs) in agonist-induced desensitization of the
µ-opioid receptor (MOPr) in brain neurons. We have studied a novel membrane-permeable, small-molecule inhibitor of GRK2 and
GRK3, Compound 101 to elucidate the role of GRK2/3 in acute agonist-induced MOPr desensitization (1).
Improved synthesis of Cmpd101 was developed in 9 steps in good overall yield. Pharmacological studies with Cmpd 101 support the
view that GRK2 and GRK3 do play a role in MOPr desensitization in LC neurons. What was surprising was that Cmpd 101 only partially
reversed the loss of MOPr function that underlies desensitization. The inability of this compound to fully reverse the loss of MOPr
function could indicate either that there are two mechanisms of MOPr desensitization, one involving GRK-mediated phosphorylation
(inhibited by Cmpd 101) and one that does not involve GRK2 and GRK3 or that, in intact neurons, for reasons that are unclear, Cmpd 101
does not completely inhibit GRK2 and GRK3.
Encouraging biological results, prompted us to synthesise analogues of Cmpd 101 using Wittig and Click chemistry. This will allow
us to better define the pharmacophore responsible for affinity and selectivity within this series. For further support, molecular
modelling studies were carried out by docking Cmpd 101 and the analogues into a crystal structure of GRK2. These new compounds are
currently under evaluation and results will be presented at the meeting.
µ-opioid receptor (MOPr) in brain neurons. We have studied a novel membrane-permeable, small-molecule inhibitor of GRK2 and
GRK3, Compound 101 to elucidate the role of GRK2/3 in acute agonist-induced MOPr desensitization (1).
Improved synthesis of Cmpd101 was developed in 9 steps in good overall yield. Pharmacological studies with Cmpd 101 support the
view that GRK2 and GRK3 do play a role in MOPr desensitization in LC neurons. What was surprising was that Cmpd 101 only partially
reversed the loss of MOPr function that underlies desensitization. The inability of this compound to fully reverse the loss of MOPr
function could indicate either that there are two mechanisms of MOPr desensitization, one involving GRK-mediated phosphorylation
(inhibited by Cmpd 101) and one that does not involve GRK2 and GRK3 or that, in intact neurons, for reasons that are unclear, Cmpd 101
does not completely inhibit GRK2 and GRK3.
Encouraging biological results, prompted us to synthesise analogues of Cmpd 101 using Wittig and Click chemistry. This will allow
us to better define the pharmacophore responsible for affinity and selectivity within this series. For further support, molecular
modelling studies were carried out by docking Cmpd 101 and the analogues into a crystal structure of GRK2. These new compounds are
currently under evaluation and results will be presented at the meeting.
Original language | English |
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Publication status | Published - 2016 |
Event | INTERNATIONAL NARCOTICS RESEARCH CONFERENCE - Bath, United Kingdom Duration: 11 Jul 2016 → … |
Conference
Conference | INTERNATIONAL NARCOTICS RESEARCH CONFERENCE |
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Country/Territory | United Kingdom |
Period | 11/07/16 → … |