Benz[f]isoquinoline analogues as high-affinity sigma ligands.
This paper describes the synthesis of some conformationally restricted 4-phenylpiperidine analogues and their affinities for the guinea pig cerebellum sigma recognition site ([3H]-DTG) and the rat striatum dopamine D2 receptor ([3H]-(-)-sulpiride) in order to develop potent selective sigma ligands as tools in the investigation of this site in psychosis. It was found that both hexa- and octahydrobenz[f]isoquinolines with lipophilic N-substituents had high affinities for the sigma site. Notably, trans-3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline (26) had an affinity of 0.25 nM making it the highest affinity sigma ligand reported to date. Moreover, it is at least 10,000-fold selective over the D2 receptor and could prove to be a valuable tool in the study of sigma sites. Other analogues such as 1H-indeno[2,1-c]pyridines and 1H-benzo[3,4]cyclohepta[1,2-c]pyridines also displayed high sigma site affinity.
Russell
M G
MG
Chemistry Department, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
Baker
R
R
Billington
D C
DC
Knight
A K
AK
Middlemiss
D N
DN
Noble
A J
AJ
D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid / Q000378:metabolism*; D017480:Receptors, sigma; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D007546:Isoquinolines; D010880:Piperidines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011957:Receptors, Opioid; D017480:Receptors, sigma; C074913:3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz(f)isoquinoline; C048151:4-phenylpiperidine