Selective protection and functionalization of morphine: synthesis and opioid receptor binding properties of 3-amino-3-desoxymorphine derivatives.
As part of an effort to identify novel opioid receptor interactive agents, we recently prepared a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino (NHC(6)H(5)) cyclazocine derivative to have subnanomolar affinity for kappa opioid receptors and a 2-fold lower affinity for mu, opioid receptors. To determine if the benefits of (substituted)amino groups could be extended to the morphine core structure, we have made five novel 3-amino-3-desoxymorphine derivatives of general structure 5 where RR'N = H(2)N, CH(3)NH, (CH(3))(2)N, C(6)H(5)NH, and C(6)H(5)CH(2)NH. Relative to morphine, these derivatives had 38-273-fold, 11-41-fold, and 10-141-fold lower affinity for mu, delta, and kappa opioid receptors, respectively. Target compounds were made via Pd-catalyzed amination of a morphine 3-trifluoromethylsulfonate substrate where the 6-OH group was protected with a tert-butyldiphenylsilyl group. To make 6-tert-butyldiphenylsilyloxymorphine selectively, a new high-yield method was developed whereby morphine was bis-silylated using normal conditions followed by selective removal of the 3-tert-butyldiphenylsilyl group with catalytic tetrabutylammonium fluoride.
Wentland
M P
MP
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180, USA. wentmp@rpi.edu
Duan
W
W
Cohen
D J
DJ
Bidlack
J M
JM
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003496:Cyclazocine / Q000031:analogs & derivatives / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009022:Morphine Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013237:Stereoisomerism
D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D009022:Morphine Derivatives; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D003496:Cyclazocine