Design, Synthesis, and Structure-activity Relationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the Human A2b Adenosine Receptor.
From: Dipartimento Farmaco-chimico, Università di Bari, via Orabona 4, I-70125 Bari, Italy. carotti@farmchim.uniba.it
Journal of medicinal chemistry
- Publish Date: Jan 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 1
- Pages: 282-99
- Medium: Print
- Language: English
- Citation (JAMA): Carotti Angelo, Cadavid Maria Isabel, Centeno Nuria B, et al. Design, Synthesis, and Structure-activity Relationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the Human A2b Adenosine Receptor.. J. Med. Chem. Jan 2006;49:282-99
Abstract
Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.
Mesh Headings (Keywords): Animals, Binding, Competitive, CHO Cells, Cell Line, Cricetinae, Drug Design, Hela Cells, Humans, Molecular Structure, Rats, Rats, Sprague-Dawley, Receptor, Adenosine A1, Receptor, Adenosine A2A, Receptor, Adenosine A2B, Receptor, Adenosine A3, Receptors, Adenosine A2, Stereoisomerism, Structure-Activity Relationship, Xanthines
Check for Full Text / PubMed Unique Identifier (PMID): 16392813
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.