Dopamine receptor ligands. Part VII [1]: novel 3-substituted 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles as ligands for the dopamine receptors.
A number of 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles 3 were synthesized with different substituents at the azepine-N position (methyl-, allyl-, 2-phenyl-ethyl-, cyclopropylmethyl- and unsubstituted). Furthermore, the indole-N-methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4-methyl-5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles were prepared which contained racemisation at the reacting C-atom. These compounds, as well as the ring-open amino-alcohols, were screened for their affinity to the hD(1)-, hD(5)-, hD(2L)-, and hD(4)-receptors (ç please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D(1)-subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl-(3c) and methyl-substituents (3 e) being the most active of the tested compounds. Based on an intracellular cAMP-assay, the unsubstituted compound (at the azepine-N position) turned out to be an agonist for the D(1)-and D(5)-subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.
Institut für Pharmazie, Pharmazeutische/Medizinische Chemie, Friedrich-Schiller Universität Jena, Germany.
Michael
M
Decker
Jochen
J
Lehmann
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D011954:Receptors, Dopamine / Q000378:metabolism*; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D001381:Azepines; D018492:Dopamine Antagonists; D007211:Indoles; D008024:Ligands; D011954:Receptors, Dopamine; D000242:Cyclic AMP