Synthesis of (+)-(1'R,2'S) and (1'S,2'R)-6,11-dimethyl-1,2,3,4,5,6 -hexahydro-3-[[2'-(alkoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2 ,6 -methano-3-benzazocin-8-ol. Comparison of the affinities for sigma 1 and opioid receptors with in the diastereoisomeric MPCB and CCB.
The synthesis and the in vitro receptor affinity for sigma 1 and opiod receptors of the two diastereoisomers of (+)-cis-MPCB namely, (+)-cis-(1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6 -hexahydro-3-[[2'-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2 ,6 -methano-3-benzazocin-8-ol, (1'S,2'R)6a and (+)-cis-(1'R,2'S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-3- [[2-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2,6-methano-3-+ ++benzazocin-8 -ol, (1'R,2'S)6a are reported. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with those of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed higher affinity for the sigma 1 sites, labeled with [3H]-(+)-pentazocine than the corresponding (-)-cis- analogs. In particular, compound (1'S,2'R)6a showed a Ki = 66.7 nM for sigma 1 receptor, associated with a good selectivity for sigma 1 with respect to kappa, mu, delta opioid receptors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support the hypothesis that the (+)-cis-N-normetazocine nucleus posses a specific enantioselectivity for sigma 1 sites, when supporting bulkier N-substituents functionalized with a carboxy ester group.
Ronsisvalle
G
G
Dipartimento di Scienze Farmaceutiche, Università di Catania, Italy.
Prezzavento
O
O
Pasquinucci
L
L
Pappalardo
M S
MS
Marrazzo
A
A
Vittorio
F
F
Carboni
L
L
Spampinato
S
S
D000818:Animals; D001921:Brain / Q000378:metabolism; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D007536:Isomerism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013329:Structure-Activity Relationship
C110285:6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-((2'-(methoxycarbonyl)-2'-phenylcyclopropyl)methyl)-2,6-methano-3-benzazocin-8-ol; D011957:Receptors, Opioid; D017480:Receptors, sigma; D003496:Cyclazocine