Discovery of a novel class of substituted pyrrolooctahydroisoquinolines as potent and selective delta opioid agonists, based on an extension of the message-address concept.
This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).
Dondio
G
G
SmithKline Beecham S.p.A., Baranzate, Milan, Italy.
Ronzoni
S
S
Eggleston
D S
DS
Artico
M
M
Petrillo
P
P
Petrone
G
G
Visentin
L
L
Farina
C
C
Vecchietti
V
V
Clarke
G D
GD
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists*; D015398:Signal Transduction; D013237:Stereoisomerism; D014649:Vas Deferens / Q000187:drug effects
C108703:2-((diethylamino)carbonyl)-6-ethyl-8a-(3-hydroxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo(2,3-g)isoquinoline; D001549:Benzamides; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D009292:Narcotic Antagonists; D010879:Piperazines; D011758:Pyrroles; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; C055382:naltrindole