Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke.
We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice. We found that the hydroxyl function in the 4'-position is crucial for improving the sodium channel blocking properties. Moreover, the stereochemistry and the topology of the N-linked side chain also influence this interaction. Indeed, the affinity is improved by an aromatic substitution in the side chain. By modifying the N substituent and the substitution pattern of the hydroxyl function, we were able to discover (2R)-[2alpha,3(S),6alpha]-1,2,3,4,5,6-hexahydro-6,11,11-tri-methyl-3-[2-(phenylmethoxy)propyl]-2,6-methano-3-benzazocin-10-ol hydrochloride. This compound was chosen as the best candidate for further pharmacological investigations.
Grauert
Matthias
M
Department of Medicinal Chemistry, Boehringer Ingelheim Pharma KG, 88397 Biberach an der Riss, and Corporate Development, Boehringer Ingelheim GmbH, 55216 Ingelheim am Rhein, Germany. Matthias.Grauert@bc.boehringer-ingelheim.com
Bechtel
Wolf D
WD
Weiser
Thomas
T
Stransky
Werner
W
Nar
Herbert
H
Carter
Adrian J
AJ
D000818:Animals; D001575:Benzomorphans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D018360:Crystallography, X-Ray; D004597:Electroshock; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D012640:Seizures / Q000188:drug therapy / Q000209:etiology; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy / Q000209:etiology; D013329:Structure-Activity Relationship; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy; D014701:Veratridine / Q000494:pharmacology
C408069:BIII 890 CL; D001575:Benzomorphans; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D018698:Glutamic Acid; D014701:Veratridine