Opioid peptides: simultaneous delta agonism and mu antagonism in somatostatin analogues.
Four isomers of the Somatostatin analogue H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) were made with beta-MePhe in position 1 and assayed for opioid binding in rat brain, biological activity in MVD and GPI bioassays, and antinociception in mouse warm-water tail flick assays. The analogues displayed varying potencies and biological activities including: simultaneous delta receptor agonism/mu receptor antagonism, mu receptor antagonism, and delta receptor agonism. These analogues demonstrated that the N-terminal residue is important for receptor potency/selectivity and signal transduction. These analogues my represent leads to therapeutic agents that yield analgesia via delta agonist effects, yet lack side effects associated with mu activity.
Bonner
G G
GG
Department of Chemistry, University of Arizona, Tucson 85721, USA.
Davis
P
P
Stropova
D
D
Ferguson
R
R
Yamamura
H I
HI
Porreca
F
F
Hruby
V J
VJ
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; C529311:CTAP octapeptide; D004745:Enkephalins; D018847:Opioid Peptides; D010446:Peptide Fragments; D010455:Peptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013004:Somatostatin; D020881:Enkephalin, D-Penicillamine (2,5)-