Dopamine/serotonin receptor ligands. Part IV [1]: synthesis and pharmacology of novel 3-benzazecines and 3-benzazonines as potential 5-HT2A and dopamine receptor ligands.
LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D1/D5 receptors and the serotonin 5-HT2A receptor. The compound consists of a 10-membered central azecine ring fused to indole on one and to benzene on the other side. To estimate the importance of the indole moiety in this highly active benz-indolo-azepine, the indole has to be removed and the "de-indolised" analog reinvestigated pharmacologically. Accordingly, we synthesized 3-benzazecines and in addition some homologuous 3-benzazonines. Methoxylated beta-phenylethylamines were treated with ethyl omega-bromo-butanoates and -pentanoates, respectively, to give the corresponding lactams which were cyclized (POCl3) and reduced (NaBH4), yielding the cis-annelated (X-ray) benzindolizines and -quinolizines. The 10- and 9-membered rings were obtained by cleavage of the central C-N bond, which was performed in the following two ways: Quarternisaion with methyl iodide and cleavage with sodium in liquid ammonia gave the NCH3 derivatives, reaction with benzyloxycarbonyl chloride/NaBH4 followed by catalytic debenzylation yielded a corresponding NH compound. Functional experiments on rat artery segments precontracted with ketanserin and radioligand binding experiments using human cloned dopamine receptor subtypes were conducted with all of the benzazecine and benzazonine derivatives. In contrast to the benz-indolo-compound LE 300 they did not show any significant affinity towards the D1, D2, D4, and D5 receptors and only moderate antagonistic activity at the 5-HT2A receptor. It can be concluded from our study that an indole moiety or at least another second aromatic system at the central azecine ring is part of the pharmacophore and thus essential for high biological activity.
El-Subbagh
Hussein
H
Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt.
Wittig
Thomas
T
Decker
Michael
M
Elz
Sigurd
S
Nieger
Martin
M
Lehmann
Jochen
J
D000818:Animals; D001391:Azo Compounds / Q000138:chemical synthesis*; D016466:CHO Cells; D006224:Cricetinae; D018360:Crystallography, X-Ray; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects
C409874:7-methyl-6,7,8,9,14,15-hexahydro-5H-benz(d)indolo(2,3-g)azecine; D001391:Azo Compounds; D018492:Dopamine Antagonists; D007211:Indoles; D008024:Ligands; D044402:Receptor, Serotonin, 5-HT2A; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists