Binding and Preliminary Evaluation of 5-Hydroxy- and 10-Hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines as Dopamine Receptor Ligands
| Autor: | José Angel Fontenla, G. Orlando, Francesco Claudi, F. Napolitani, G. M. Cingolani, L. Brunetti, E. Rosa, Gisela Montenegro, A. Di Stefano, M. E. Rivas, B. Michelotto, Gianfabio Giorgioni |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Models Molecular Agonist Stereochemistry medicine.drug_class In Vitro Techniques Ligands Binding Competitive Chemical synthesis Cell Line Radioligand Assay Structure-Activity Relationship chemistry.chemical_compound Pituitary Gland Anterior Dopamine Drug Discovery medicine Animals Humans Rats Wistar Receptor Receptors Dopamine D2 Chemistry Receptors Dopamine D1 Isoquinolines Corpus Striatum Prolactin Rats Dopamine D2 Receptor Antagonists Dopamine receptor Dopamine Agonists Dopamine Antagonists Molecular Medicine Ethylamine Pharmacophore medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 43:599-608 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm991034o |
| Popis: | The N-methyl, N-ethyl, and N-n-propyl derivatives of 5-hydoxy- and 10-hydroxy-2,3,12,12a-tetrahydro-1H-[1]benzoxepino[2,3, 4-ij]isoquinolines were prepared as monophenolic ligands for the dopamine receptor and evaluated for their affinity at D(1)-like and D(2)-like subtypes. All compounds showed very low D(1) affinities. This could be ascribed to the absence of a catechol nucleus or of the beta-phenyldopamine pharmacophore. Only the N-methyl-5-hydroxy- (5a), N-methyl-10-hydroxy- (6a), and N-methyl-4-bromo-10-methoxy-2,3, 12,12a-tetrahydro-1H-[1]benzoxepino[2,3,4-ij]isoquinolines (26a) bound the D(2) receptors with low affinity, in the same range as dopamine. In compounds 5a and 6a, the 2-(3-hydroxyphenyl)ethylamine moiety does not meet the requirements of the D(2) agonist pharmacophore: namely, the 2-(3-hydroxyphenyl)ethylamine does not reach the trans, fully extended conformation. The three compounds did not interact with recombinant human D(4) receptors, and only 5a showed low affinity for rat recombinant D(3) receptors. Analysis of the influence of Na(+) on [(3)H]spiperone binding showed that 5a displays a potential dopamine D(2) agonist profile, whereas 6a probably has a dopamine D(2) antagonist activity. The D(2) agonist activity of 5a was proved by the effects on prolactin release from primary cultures of rat anterior pituitary cells. |
| Databáze: | OpenAIRE |
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