Synthesis and in vitro evaluation of 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: high-affinity ligands for the N,N'-di-o-tolylguanidine-labeled sigma binding site.
A series of 5,6,7,8,9,10-hexahydro-7,10-iminocyclo[b]indoles substituted at the 5 and/or 11 positions was synthesized from tropinone. Affinity for sigma binding sites was determined using [3H]-N,N'-di-o-tolylguanidine ([3H]DTG) and [3H]-(+)-3-(3-hydroxyphenyl)-N-1-propylpiperidine ([3H]-(+)-3-PPP) and for the dopamine D2 receptor labeled with [3H]sulpiride. Nearly all compounds studied in this series possessed a higher affinity for [3H]DTG than [3H]-(+)-PPP-labeled sigma sites, suggesting that [3H]DTG and [3H]-(+)-3-PPP radioligands label pharmacologically distinct sigma binding sites, as reported previously. Substitution at the 11 position with side chains containing a four-carbon tether resulted in compounds having the highest affinity for the [3H]DTG-labeled sigma site. The most potent and selective member of this series was 11-[4-(2-furanyl)butyl]-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept [b] indole (40). Enantioselectivity was investigated by preparing the (+)- and (-)-isomers of 40. These studies revealed that (+)-40 was more potent at the [3H]-DTG-labeled sigma site whereas (-)-40 had a higher affinity at sigma sites labeled with [3H]-(+)-PPP. Racemic 40 was observed to possess a higher affinity than either of its respective enantiomers at both the [3H]DTG- and [3H]-(+)-3-PPP-labeled sites, suggesting an allosteric interaction.
Mewshaw
R E
RE
Scios-Nova Inc., Baltimore, Maryland 21224-6522.
Sherrill
R G
RG
Mathew
R M
RM
Kaiser
C
C
Bailey
M A
MA
Karbon
E W
EW
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002243:Carbolines / Q000138:chemical synthesis* / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010880:Piperidines / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013469:Sulpiride / Q000378:metabolism; D014961:X-Ray Diffraction
D002243:Carbolines; D006146:Guanidines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D017480:Receptors, sigma; D013469:Sulpiride; C026539:preclamol; C050232:1,3-ditolylguanidine