[L-Ala3]DPDPE: a new enkephalin analog with a unique opioid receptor activity profile. Further evidence of delta-opioid receptor multiplicity.
To investigate delta-opioid receptor topography near the 3-position of [D-Pen2,D-Pen5]enkephalin (DPDPE), a series of small-group 3-position analogs of DPDPE have been synthesized and assayed for binding potencies and in vitro biological activities. L-Amino acid substitutions at this position are highly favored over D-amino acid substitutions, with the smallest, [L-Ala3]DPDPE (DPADPE), being the most favored in the series investigated. [L-Ala3]DPDPE is nearly as delta-potent and more delta-selective in both rat brain binding (18 nM vs [3H] [p-ClPhe4]DPDPE and mu/delta = 610) and peripheral bioassays (12 nM in the MVD and GPI/MVD = 4500) when compared to DPDPE (8.5 nM, mu/delta = 73 and 4.1 nM, GPI/MVD = 1800, respectively). Whereas DPDPE is a potent analgesic when given icv, [L-Ala3]DPDPE is only a weak analgesic. However, [L-Ala3]DPDPE has been found to antagonize DPDPE, but not Deltorphin II, in a moderately potent (pA2 = 5.7) and selective fashion in vivo. Thus, [L-Ala3]DPDPE is a fairly potent agonist at peripheral delta receptors and is a moderately potent (mixed) antagonist of delta 1 receptors in the brain. It appears that [L-Ala3]DPDPE does not interact in any significant manner with delta 2 or mu receptors in the brain.
Haaseth
R C
RC
Department of Chemistry, University of Arizona, Tucson 85721.
Horan
P J
PJ
Bilsky
E J
EJ
Davis
P
P
Zalewska
T
T
Slaninova
J
J
Yamamura
H I
HI
Weber
S J
SJ
Davis
T P
TP
Porreca
F
F
D000595:Amino Acid Sequence; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004745:Enkephalins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C087554:enkephalin, Pen(2,5)-Ala(3)-; D020881:Enkephalin, D-Penicillamine (2,5)-