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Dopamine/Serotonin Receptor Ligands. Part IV [1]: Synthesis and Pharmacology of Novel 3‐Benzazecines and 3‐Benzazonines as Potential 5‐HT 2A and Dopamine Receptor Ligands
Author(s) -
ElSubbagh Hussein,
Wittig Thomas,
Decker Michael,
Elz Sigurd,
Nieger Martin,
Lehmann Jochen
Publication year - 2002
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200212)335:9<443::aid-ardp443>3.0.co;2-u
Subject(s) - chemistry , indole test , stereochemistry , moiety , ketanserin , dopamine , receptor , radioligand , serotonin , 5 ht receptor , biochemistry , neuroscience , biology
LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D 1 /D 5 receptors and the serotonin 5‐HT 2A 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 β‐phenylethylamines were treated with ethyl ω‐bromo‐butanoates and ‐pentanoates, respectively, to give the corresponding lactams which were cyclized (POCl 3 ) and reduced (NaBH 4 ), 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 NCH 3 derivatives, reaction with benzyloxycarbonyl chloride/NaBH 4 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 D 1 , D 2 , D 4 , andD 5 receptors and only moderate antagonistic activity at the 5‐HT 2A 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.