Opioid and melanocortin receptors: do they have overlapping pharmacophores?
We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the delta opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the delta opioid receptor (Ki = 0.38 nM in binding assay, EC(50) = 0.48 nM in GTP-gamma-S binding assay, IC(50) = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC(50) = 2.3 muM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
Yeon Sun
YS
Lee
Richard S
RS
Agnes
James P
JP
Cain
Vinod
V
Kulkarni
Minying
M
Cai
Christine
C
Salibay
Kathy
K
Ciano
Ravil
R
Petrov
Alexander
A
Mayorov
Josef
J
Vagner
Dev
D
Trivedi
Peg
P
Davis
Shou-wu
SW
Ma
Josephine
J
Lai
Frank
F
Porreca
Ruben
R
Vardanyan
Victor J
VJ
Hruby
D001667:Binding, Competitive; D002460:Cell Line; D000242:Cyclic AMP / Q000032:analysis; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008024:Ligands; D011869:Radioligand Assay; D044104:Receptor, Melanocortin, Type 3 / Q000819:agonists* / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D044104:Receptor, Melanocortin, Type 3; D017465:Receptors, Opioid, delta; D000242:Cyclic AMP