Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogues for opioid activity.
An enkephalin analogue coupled to 'aminofentanyl' has been synthesized and tested for biological activities at the mu and delta opioid receptors. Aminofentanyl which represents a structural derivative of fentanyl has been synthesized by acylation of 1-(2-phenethyl)-4-(N-anilino)piperidine with phthaloyl protected beta-alaninyl chloride in the presence of DIPEA, followed by deprotection with hydrazine hydrate. Aminofentanyl has also been successfully acylated with ethyl isocyanate, various acid anhydrides, to further investigate structure-activity relationships of these new fentanyl derivatives. Among the new derivatives compound 7 which carries a Tyr-D-Ala-Gly-Phe opioid message sequence showed good opioid affinity (1 nM at both delta and mu opioid receptors) and bioactivity (34.9 nM in MVD and 42 nM in GPI/LMMP bioassays).
Petrov
Ravil R
RR
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA.
Vardanyan
Ruben S
RS
Lee
Yeon S
YS
Ma
Shou-wu
SW
Davis
Peg
P
Begay
Lucinda J
LJ
Lai
Josephine Y
JY
Porreca
Frank
F
Hruby
Victor J
VJ
D000818:Animals; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009294:Narcotics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010847:Picolines; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship
D009294:Narcotics; D010847:Picolines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C015672:2-amino-4-picoline; D005283:Fentanyl