Further studies on lead compounds containing the opioid pharmacophore Dmt-Tic.
Some reference opioids containing the Dmt-Tic pharmacophore, especially the delta agonists H-Dmt-Tic-Gly-NH-Ph (1) and H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid (4) (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the -NH-Ph and N(1)H-Bid hydrogens in the inductions of delta agonism. The results provide the following conclusions: (i) Asp increases delta selectivity by lowering the mu affinity; (ii) -NH-Ph and N(1)H-Bid nitrogens methylation transforms the delta agonists into delta antagonists; (iii) the substitution of Gly with L-Asp/D-Asp in the delta agonist H-Dmt-Tic-Gly-NH-Ph gave delta antagonists; the same substitution in the delta agonist H-Dmt-Tic-NH-CH2-Bid yielded more selective agonists, H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid and H-Dmt-Tic-NH-(R)CH(CH2-COOH)-Bid; (iv) L-Asp seems important only in functional bioactivity, not in receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid(N(1)-Me) (10) evidenced analgesia similar to 4, which was reversed by naltrindole only in the tail flick. 4 and 10 had opposite behaviours in mice; 4 caused agitation, 10 gave sedation and convulsions.
Balboni
Gianfranco
G
Department of Toxicology, University of Cagliari, I-09124 Cagliari, Italy. gbalboni@unica.it
Fiorini
Stella
S
Baldisserotto
Anna
A
Trapella
Claudio
C
Sasaki
Yusuke
Y
Ambo
Akihiro
A
Marczak
Ewa D
ED
Lazarus
Lawrence H
LH
Salvadori
Severo
S
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D013623:Tail / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism*
C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D000700:Analgesics; D004151:Dipeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines