Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors.
The phenolic group of the potent mu and kappa opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with para-substituents in the benzene ring. These compounds are highly potent mu and kappa ligands, e.g., p-methoxyphenylaminocyclorphan showing a K(i) of 0.026 nM at the mu receptor and a K(i) of 0.03 nM at the kappa receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans.
Decker
Michael
M
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.
Si
Yu-Gui
YG
Knapp
Brian I
BI
Bidlack
Jean M
JM
Neumeyer
John L
JL
D001665:Binding Sites; D008024:Ligands; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists; D013329:Structure-Activity Relationship
D008024:Ligands; D009019:Morphinans; D009292:Narcotic Antagonists; C520649:butorphan; C084603:cyclorphan