Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior.
3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
András
A
Váradi
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Gina F
GF
Marrone
Torrey Pines Institute for Molecular Studies , 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
Shainnel O
SO
Eans
Torrey Pines Institute for Molecular Studies , 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
Michelle L
ML
Ganno
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Joan J
JJ
Subrath
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Valerie
V
Le Rouzic
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Amanda
A
Hunkele
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Gavril W
GW
Pasternak
Torrey Pines Institute for Molecular Studies , 11350 SW Village Parkway, Port St. Lucie, Florida 34987, United States.
Jay P
JP
McLaughlin
Molecular Pharmacology and Chemistry Program, Department of Neurology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
Susruta
S
Majumdar
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000737:chemistry; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000494:pharmacology; D011897:Random Allocation; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D012201:Reward; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
C000610195:17-cyclopropylmethyl-3-hydroxy-4,5-epoxy-7,8-en-6-((3'-iodo)benzamido)morphinan; D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D009019:Morphinans; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C404943:Oprm protein, mouse; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C539739:Rora protein, mouse; C570718:iodobenzoylnaltrexamide; D009271:Naltrexone; D003042:Cocaine
IBNtxA; MP1104; Opioid analgesics; cocaine addiction; delta; kappa