Synthesis of novel diazatricyclodecanes (DTDs). Effects of structural variation at the C3' allyl end and at the phenyl ring of the cinnamyl chain on mu-receptor affinity and opioid antinociception.
Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1(2,5)]decane (1a) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.0(3,8)]decane (2a), in which the cinnamyl moiety was replaced by various aralkenyl chains, 1b-l and 2b-l, respectively, have been synthesized and evaluated for their ability to bind to the opioid mu-, delta- and kappa-receptors. The binding data indicated that compounds 1b,d,e,h and 2b,d,e,f,h,i showed a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. Selected DTDs, the pairs 1,2b, 1,2e and 1,2h, were also evaluated for analgesic effect. In the hot plate test, only 1b given ip was found to have similar opioid antinociception and chronic tolerance as morphine.
Pinna
Gérard Aimè
GA
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy. pinger@uniss.it
Cignarella
Giorgio
G
Ruiu
Stefania
S
Loriga
Giovanni
G
Murineddu
Gabriele
G
Villa
Stefania
S
Grella
Giuseppe Enrico
GE
Cossu
Gregorio
G
Fratta
Walter
W
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry*; D043822:Cyclodecanes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D010147:Pain Measurement; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
D000701:Analgesics, Opioid; D001391:Azo Compounds; D002934:Cinnamates; D043822:Cyclodecanes; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu