PubMed · 5730149
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1968-11-01. Influenza immunization.. https://pubmed.ncbi.nlm.nih.gov/5730149/
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We hypothesized that uncompetitive NMDA glutamate receptor antagonists memantine (2,5-dimethyl-1-adamantanamine), and amino-alkyl-cyclohexane compounds: MRZ 2/579 (1-amino-1,3,3,5,5-pentamethylcyclohexane HCl), MRZ 2/600 (1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane HCl), and MRZ 2/615 (1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane HCl), all derivatives of amantadine (1-adamantanamine HCl), would inhibit the energy-dependent uptake of amantadine into rat renal tubules. All compounds displayed a concentration-dependent inhibition of amantadine uptake in the proximal and distal renal tubules. MRZ 2/579 showed a novel distal tubule selectivity of inhibition (P < 0.001). At a therapeutic amantadine concentration, bicarbonate-dependent transporter inhibition selectivity was observed with all compounds (P < 0.05) except MRZ 2/600, the only compound with a sterically bulky group next to the amino group of the cyclohexane ring structure. Steric hindrance around the ionized amino group of the cyclohexane ring appears to prevent bicarbonate-mediated organic cation transport. Furthermore, the distal tubule inhibition selectivity with MRZ 2/579 provides a novel tool to study the relative importance of organic cation transporters (OCTs) in proximal vs. distal renal tubules.
Amantadine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to increase dopamine synthesis and release in the striatum, is frequently associated with L-DOPA in the treatment of Parkinson's disease. However, the biochemical mechanisms involved in the effect of amantadine and the consequences of its repetitive administration on the modulation of striatal dopamine transmission still need to be clarified. We have investigated the effects of short-term amantadine treatments on the expression of dopamine receptors and the functional coupling to G proteins in rat striatal membranes. Dopamine-induced stimulation of guanosine 5'-[gamma-35S]triphosphate ([35S]GTPgammaS) binding was significantly enhanced (40%) in striatum homogenates from rats treated for 4 days with amantadine (40 mg/kg, i.p.) compared to vehicle-treated animals. This effect was specific for dopamine receptors and was transient as no significant modifications were observed when animals were treated for either 2 or 7 days. Administration of amantadine did not directly affect the animal behaviour. However, treated animals exhibited hypersensitive dopamine transmission since rats treated for 4 days showed exacerbated responses to a single apomorphine administration (enhanced locomotor activity and reduced stereotypy). Since the effects of amantadine administration differ from those usually observed with direct dopamine receptor agonists or other NMDA receptor antagonists, we suggest that multiple biochemical mechanisms contribute to the modulation of dopamine transmission by amantadine.
Two bridgehead-alkylated 2-thiaadamantanes (1,5-dimethyl and 1-methyl) have been identified in petroleum; these compounds give clues to sulfurisation processes affecting petroleum which has undergone high thermal stress.