Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen)

• Published in: Journal of medicinal chemistry 1991-05, Vol.34 (5), p.1675-1692
• Main Authors: HSON MOU CHANG, KUK YING CHUI, FA WAH LAU TAN, YUN YANG, ZENG PEI ZHONG, CHI MING LEE, HING LEUNG SHAM, WONG, H. N. C
• Format: Article
• Language: English
• Subjects: 550201 - Biochemistry- Tracer Techniques; AFFINITY; ANIMALS; BASIC BIOLOGICAL SCIENCES; BIOCHEMICAL REACTION KINETICS; Biological and medical sciences; BODY; BRAIN; Brain - drug effects; Brain - metabolism; CATTLE; CELL CONSTITUENTS; CELL MEMBRANES; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM AGENTS; Chemical Phenomena; Chemistry; DOMESTIC ANIMALS; DRUGS; Drugs, Chinese Herbal; Flunitrazepam - metabolism; General pharmacology; HYDROGEN COMPOUNDS; ISOTOPE APPLICATIONS; KINETICS; LIGANDS; MAMMALS; Medical sciences; MEMBRANE PROTEINS; MEMBRANES; NERVOUS SYSTEM; ORGANIC COMPOUNDS; ORGANS; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phenanthrenes - chemical synthesis; Phenanthrenes - pharmacology; PROTEINS; PSYCHOTROPIC DRUGS; REACTION KINETICS; RECEPTORS; Receptors, GABA-A - drug effects; Receptors, GABA-A - metabolism; RUMINANTS; Structure-Activity Relationship; STRUCTURE-ACTIVITY RELATIONSHIPS; TRACER TECHNIQUES; TRANQUILIZERS; Tranquilizing Agents - chemical synthesis; Tranquilizing Agents - pharmacology; Tritium; TRITIUM COMPOUNDS; VERTEBRATES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00109a022

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).