N-(Iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines: synthesis and adrenergic and dopaminergic activity studies.
A series of N-(iodopropenyl)-octahydrobenzo[f]- and -[g]quinolines was synthesized and assayed in vitro for their dopaminergic and alpha-adrenergic activity. Structure-activity relationship (SAR) analysis revealed that the tested benzoquinolines exhibited activity at the D1 rather than the D2 receptor sites in contrast to the D2 receptor subfamily activity reported for their aminotetralin congeners. N-Iodopropenyl substitution was apparently a decisive factor for D1 activity independent of ring substitution pattern. Considering the structural factors influencing alpha-adrenergic activity, in a general trend, N-iodopropenyl analogues were alpha1-active, with the ring-hydroxylated congeners exhibiting the highest affinity. Affinity to the alpha2 receptor was even higher with no detectable trend of SAR. However, a combination of the linear arrangement of the [g]-ring system, combined with the ring hydroxyl and the N-iodopropenyl substitution in compound 5c, resulted in a significant enhancement of alpha2 activity in this series as demonstrated by an IC50 value of 0.5 nM. A new synthetic approach to the [g]benzoquinoline system is also described.
Division of Organic Chemistry, Department of Chemistry, and Laboratory of Pharmacology, School of Medicine, University of Crete, Iraklion 71 409, Crete, Greece.
N
N
Tagmatarchis
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K
Thermos
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HE
Katerinopoulos
D018663:Adrenergic Agents; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D015259:Dopamine Agents; D066298:In Vitro Techniques; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013329:Structure-Activity Relationship
C115073:6-hydroxy-1,2,3,4,4a,5,10,10a-octahydro-N-(3'-iodo-2'-propenyl)benzo(g)quinoline; D018663:Adrenergic Agents; D015259:Dopamine Agents; D011804:Quinolines; D011942:Receptors, Adrenergic, alpha; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2