Synthesis and biological activity of a novel methylamine-bridged enkephalin analogue (MABE): a new route to cyclic peptides and peptidomimetics.
The synthesis and biological activity of a methylamine-bridged enkephalin analogue (MABE) is presented. The key step in the synthesis of the target compound involves the ring opening of Cbz-d-serine beta-lactone with Boc-Phe-NHCH2CH2NHCH3. Further synthetic elaboration of the resulting building block yielded compound 1 (MABE, Tyr-c[(NbetaCH3)-D-A2pr-Gly-Phe-NHCH2CH2-], where A2pr is a 2,3-diaminopropionic acid residue). Utilizing a combination of NMR and molecular modeling, the structure-biological activity relationships for compound 1 were studied. Using an in vitro isolated receptor assay, MABE was found to have affinities for isolated mu delta, and kappa opioid receptors of 1.6, 2.1, and 340 nM, respectively. By an in vivo thermal escape assay, MABE was found to have an ED50 of 0.027 microg in the rat when administered intrathecally. This effect was reversed by naloxone. By comparison, DAMGO, morphine, and DPDPE were found to yield ED50 values of 0.14, 2.4, and 54 microg, respectively, in the same assay.
Shreder
K
K
Department of Chemistry and Biochemistry, 9500 Gilman Drive, University of California at San Diego, La Jolla, California 92093-0343, USA.
Zhang
L
L
Dang
T
T
Yaksh
T L
TL
Umeno
H
H
DeHaven
R
R
Daubert
J
J
Goodman
M
M
D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004924:Escape Reaction / Q000187:drug effects; D006801:Humans; D008297:Male; D008744:Methylamines / Q000737:chemistry*; D018716:Molecular Mimicry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000096:biosynthesis / Q000378:metabolism*
D000701:Analgesics, Opioid; D008744:Methylamines; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C113172:tyrosyl-cyclo(N-methyl)-alanyl-alanyl-2,3-diaminopropionic acid-glycyl-phenylalanyl-NH-ethyl-; C027451:methylamine