Synthesis of N-n-propyl-N-(2-arylethyl)-5-(1H-benzimidazol-2-thione)-eth ylamines and related compounds as potential dopaminergic ligands.
Twelve different N-n-propyl-N-(2-arylethyl)-5-(1H-benzimidazol-2-thione)-ethy lamines and 12 related heterocyclic congeners were synthesized with the aim of creating new high affinity dopaminergic ligands. Upon thorough chemical analysis they were evaluated for their affinity towards the D-1 and the D-2 dopamine receptors (DAR) by in vitro binding assay using synaptosomal membranes of the bovine caudate nuclei and [3H]SCH 23390 (R (+)-7-chloro-8-hydroxy-3-methyl-1-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) (D-1 selective) and [3H]spiperone (D-2 selective) as the radioligands. None of the synthesized compounds expressed affinity for the binding to the D-1 DAR Compounds 11e, 11j, 11l, 12b, 12d, 13a, 13d, 14a, and 14d were also inactive competitors of [3H] spiperone binding to the D-2 DAR. However, 1H-benzimidazol-2-thione derivatives 11k, 11h, and 11f and 1, 4-di-hydroquinoxalin-2,3-dione derivative 12c (in this rank order of potencies) acted as strong competitors of [3H] spiperone binding to the D-2 receptors under conditions that prevented radioligand binding to serotonin 5HT(2) receptors. Relationship between the structure and affinities of the new ligands for the binding to the D-2 DAR as well as the demands of the receptor itself for the interaction with the new compounds are discussed.
Soskic
V
V
Institute for Biological Research, Faculty of Chemistry, Belgrade, Yugoslavia.
Dukić
S
S
Dragović
D
D
Joksimović
J
J
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000378:metabolism; D005021:Ethylamines / Q000138:chemical synthesis* / Q000378:metabolism; D008024:Ligands; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013871:Thiones / Q000138:chemical synthesis* / Q000378:metabolism
D001552:Benzazepines; D001562:Benzimidazoles; D018491:Dopamine Agonists; D005021:Ethylamines; D008024:Ligands; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013871:Thiones; D013134:Spiperone