Polyamine-like actions of aminoglycosides and aminoglycoside derivatives at NMDA receptors.
Recent pharmacological studies indicate that aminoglycoside-induced hearing loss may be an excitotoxic process modulated by a polyamine-like activation of cochlear NMDA receptors. Aminoglycoside antibiotics are constituted by a series of glycosidically linked aminocyclitols and aminosugars. We report here on the actions of these individual aminocyclitols and aminosugars on wild type NMDA receptors from rat brain. Compared to the parent molecules, neither aminocyclitols (e.g., 2-deoxystreptamine, streptamine, and streptidine) nor aminosugars (e.g., D-glucosamine and kanosamine) were effective at enhancing [3H]dizocilpine ([3H]MK-801) binding or inhibiting [3H]ifenprodil at NMDA receptors. Moreover, the appropriate combinations of aminosugars and aminocyclitols did not reconstitute the activity of the parent aminoglycoside at NMDA receptors. These data indicate that the polyamine-like actions of aminoglycosides are attributable to the conformation of the parent molecule rather than a particular amine containing constituent. Thus, it may be possible to synthesize or isolate aminoglycoside antibiotics devoid of ototoxicity.
Segal
J A
JA
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA. segalj@lilly.com
Skolnick
P
P
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002240:Carbohydrate Sequence; D016291:Dizocilpine Maleate / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007612:Kanamycin / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009355:Neomycin / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D013096:Spermine / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000900:Anti-Bacterial Agents; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D007612:Kanamycin; D016291:Dizocilpine Maleate; D009355:Neomycin; C010739:ifenprodil