TY - JOUR
T1 - Opioid affinity and selectivity of 4-hydroxy-3-methoxyindolomorphinan analogues related to naltrindole
AU - Coop, Andrew
AU - Rothman, Richard B.
AU - Dersch, Christina
AU - Partilla, John
AU - Porreca, Frank
AU - Davis, Peg
AU - Jacobson, Arthur E.
AU - Rice, Kenner C.
PY - 1999/5/6
Y1 - 1999/5/6
N2 - To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'- indolomorphinan (13) was an exception, displaying excellent 5 binding selectivity (δ K(i) = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-χ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.
AB - To investigate the effect of the introduction of a 4-phenolic substituent on the δ opioid affinity and selectivity of the indolomorphinans, a range of 4-phenolic analogues of naltrindole were prepared and evaluated in in vitro assays. Although the majority of the ligands displayed poor affinity for all three opioid receptors (μ, κ, δ), 17-cyclopropylmethyl-6,7-didehydro-4-hydroxy-3-methoxy-6,7:2',3'- indolomorphinan (13) was an exception, displaying excellent 5 binding selectivity (δ K(i) = 7 nM, μ/δ = 1900, μ/κ = 1130). GTP-χ-S functional assays showed 13 to be a selective δ antagonist, albeit with lower potency than naltrindole. Although the reason for the unique profile of 13 could not be determined, these results validate our approach of introducing groups into the indolomorphinans that are known to reduce μ activity, to obtain increased δ selectivity.
UR - http://www.scopus.com/inward/record.url?scp=0033528829&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033528829&partnerID=8YFLogxK
U2 - 10.1021/jm9807003
DO - 10.1021/jm9807003
M3 - Article
C2 - 10229636
AN - SCOPUS:0033528829
SN - 0022-2623
VL - 42
SP - 1673
EP - 1679
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -