New paradigms and tools in drug design for pain and addiction.
New modalities providing safe and effective treatment of pain, especially prolonged pathological pain, have not appeared despite much effort. In this mini-review/overview we suggest that new paradigms of drug design are required to counter the underlying changes that occur in the nervous system that may elicit chronic pain states. We illustrate this approach with the example of designing, in a single ligand, molecules that have agonist activity at mu and delta opioid receptors and antagonist activities at cholecystokinin (CCK) receptors. Our findings thus far provide evidence in support of this new approach to drug design. We also report on a new biophysical method, plasmon waveguide resonance (PWR) spectroscopy, which can provide new insights into information transduction in G-protein coupled receptors (GPCRs) as illustrated by the delta opioid receptor.
Hruby
Victor J
VJ
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA. hruby@u.arizona.edu
Porreca
Frank
F
Yamamura
Henry I
HI
Tollin
Gordon
G
Agnes
Richard S
RS
Lee
Yeon Sun
YS
Cai
Minying
M
Alves
Isabel
I
Cowell
Scott
S
Varga
Eva
E
Davis
Peg
P
Salamon
Zdzislaw
Z
Roeske
William
W
Vanderah
Todd
T
Lai
Josephine
J
D016739:Behavior, Addictive / Q000188:drug therapy*; D015195:Drug Design; D018847:Opioid Peptides / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D018710:Pain Clinics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D018847:Opioid Peptides; D043562:Receptors, G-Protein-Coupled