Replenishment of brain adenosine triphosphate content by morphinan-type N-methyl-D-asparatate receptor antagonists, dextrorphan and dextromethorphan through the activation of adenylate kinase.
The in vitro effects of four N-methyl-D-aspartate (NMDA) receptor antagonists, dextrorphan, (DX, CAS 125-73-5), dextromethorphan, (DM, CAS 125-71-3), dizocilpine (CAS 77086-21-6) and (+/-) 2-amino-7-phosphonoheptanoate (AP-7, CAS 85797-13-3) on rat brain adenylate kinase (AK) have been studied. DM was the most active of the four compounds in increasing rat brain AK activity. DX was slightly less active than DM, while the most potent NMDA antagonist, dizocilpine was somewhat weaker than the above two morphinan analogs (DX and DM). For AP-7, the AK activity was unchanged. The results may indicate that a causal relation cannot be made between the activation of the AK by these compounds and their ability to act as NMDA antagonists. When DX was added, the Km and Vmax values of the enzyme for ADP as a substrate decreased and increased, respectively, possibly reflecting an affinity change for the enzyme-substrate interaction by DX. The observed increase in the AK activity by the morphinan-type NMDA antagonists in vitro might result in their preserving effects on cerebral neuron integrity under the conditions where cerebral energy metabolism is disturbed. This assumption was at least partly confirmed in in vivo tests in which DX, unlike dizocilpine, increased ATP content of the brain in mice under the influence of hypoxia exerted by i.v. injection of KCN.
Himori
N
N
Department of Pharmacology, Nippon Research Center, Kamakura, Japan.
Imai
M
M
Akaike
N
N
Matsukura
T
T
Watanabe
H
H
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives*; D000255:Adenosine Triphosphate / Q000032:analysis*; D000263:Adenylate Kinase / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003915:Dextromethorphan / Q000494:pharmacology; D003917:Dextrorphan / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D009019:Morphinans / Q000494:pharmacology*; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000596:Amino Acids; D009019:Morphinans; D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D016291:Dizocilpine Maleate; D003915:Dextromethorphan; D015763:2-Amino-5-phosphonovalerate; D000255:Adenosine Triphosphate; D000263:Adenylate Kinase; D011190:Potassium Cyanide; C031231:2-amino-7-phosphonoheptanoic acid