Asymmetric synthesis of 9-alkyl-2-benzyl-6,7-benzomorphans: characterization as novel sigma receptor ligands.
A convenient enantioselective synthesis of (1R,5R,9R)- and (1S,5S, 9S)-9-alkyl-2-benzyl-6,7-benzomorphans (2a-c) which starts with naphthaldehyde is described. These compounds were designed to gain additional information on the structure-sigma binding relationship of the 6,7-benzomorphan class of sigma ligands. In contrast to pentazocine and most 6,7-benzomorphans, the (1R,5R,9R)-isomers of 2a-c showed greater affinity for the sigma(1) receptor than the (1S, 5S,9S)-isomers. Despite reversal of enantioselectivity at the sigma(1) sites, moderate affinity and enantioselectivity at the sigma(2) sites [greater affinity for (1R,5R,9R)-isomers than (1S,5S, 9S)-isomers] were maintained. A comparison of the binding affinities of 2a-c to the more conformationally flexible trans-2-alkyl-1-benzaminoethyl-1,2-dihydronaphthalenes (10a-c) suggested that the relatively rigid structure of 2a-c played an important part in their sigma(1) binding properties. These compounds, particularly (1R,5R,9R)-2-benzyl-9-methyl-6,7-benzomorphan [(-)-2a], which has a K(i) value of 0.96 nM, will be useful in further characterization of the sigma(1) receptor.
Carroll
F I
FI
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Bai
X
X
Dehghani
A
A
Mascarella
S W
SW
Williams
W
W
Bowen
W D
WD
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C401386:2-benzyl-9-methyl-6,7-benzomorphan; D001575:Benzomorphans; D008024:Ligands; D017480:Receptors, sigma; C101491:sigma1-binding protein, rat