6β-Acetoxynortropane: A Potent Muscarinic Agonist with Apparent Selectivity toward M2-Receptors
| Autor: | John W. Daly, Xue-Feng Pei, William L. Padgett, Barbara Badio, Tara H. Gupta |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Agonist
Nortropanes Stereochemistry medicine.drug_class CHO Cells Muscarinic Agonists Receptors Nicotinic Phosphatidylinositols Muscarinic agonist Partial agonist Structure-Activity Relationship chemistry.chemical_compound Cricetinae Drug Discovery medicine Animals Humans Enzyme Inhibitors Receptor IC50 Cerebral Cortex Receptor Muscarinic M3 Receptor Muscarinic M2 Receptor Muscarinic M4 Ligand binding assay Receptor Muscarinic M1 Tropane Muscarinic acetylcholine receptor M2 Receptors Muscarinic Rats chemistry Adenylyl Cyclase Inhibitors Molecular Medicine Guanosine Triphosphate |
| Zdroj: | Journal of Medicinal Chemistry. 41:2047-2055 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of tropane derivatives, related in structure to baogongteng A (1), an alkaloid from a Chinese herb, were synthesized. 6beta-Acetoxynortropane (5) had weak affinity (Ki 22 microM) for central (M1) muscarinic receptors in a [3H]quinuclidinyl benzilate binding assay but had extremely high affinity (Ki 2.6 nM) and selectivity for M2-muscarinic receptors expressed in CHO cells. It had 13-fold lower affinity for M4-receptors, 260-fold lower affinity for M3-receptors, and 8200-fold lower affinity for M1-receptors expressed in CHO cells. The 6beta-carbomethoxy analogue (14) of baogongteng A had only weak affinity for M2-muscarinic receptors, as did 6beta-carbomethoxynortropane (13) and 6beta-acetoxytropane (4). In transfected CHO cells, 6beta-acetoxynortropane (5) was an agonist at M2-receptors, based on a GTP-elicited decrease in affinity, and a full agonist with an IC50 of 11 nM at M4-receptors, based on inhibition of cyclic AMP accumulation, while being a full agonist at M1-receptors with an EC50 of 23 nM and a partial agonist at M3-receptors with an EC50 of 3.6 nM, based in both cases on stimulation of phosphoinositide breakdown. All of the 16 tropane derivatives had weak affinities for central alpha4beta2-nicotinic receptors with 6beta-carbomethoxynortropane (13) having the highest affinity, which was still 150-fold less than that of nicotine. 6beta-Acetoxynortropane (5) represents a potent muscarinic agonist with apparent selectivity toward M2-receptors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|