El-Subbagh, Hussein and Wittig, Thomas and Decker, Michael and Elz, Sigurd and Nieger, Martin and Lehmann, Jochen (2002) 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. ARCHIV DER PHARMAZIE, 335 (9). pp. 443-448. ISSN 0365-6233, 1521-4184
Full text not available from this repository. (Request a copy)Abstract
LE 300 represents a structurally novel type of antagonist acting preferentially at the dopamine D-1/D-5 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-phenylethyl-amines 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 D-1, D-2, D-4, and D-5 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | QUATERNARY AMMONIUM-SALTS; DERIVATIVES; PHOTOSOLVOLYSIS; ANTAGONIST; SEROTONIN; CLONING; 3-benzazonine; 3-benzazecine; 5-HT2A ligand; dopamine receptor ligand; LE 300 |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Sep 2021 06:28 |
| Last Modified: | 29 Sep 2021 06:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/39701 |
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