Studies on the interaction of aquahydroxocobinamide with 5-aminotetrazole

Abstract

Here we show that 5-aminotetrazole (ATZ) is capable of moderately strong binding with aquahydroxocobinamide ((H₂O)(HO^-)Cbi). At pH 7.4, 25.0 °C, the reaction of (H₂O)(HO^-)Cbi with a two-fold excess of ATZ produces a mixture of complexes with one (a major fraction) having two ATZ ligands, and a minor fraction of (H₂O)(HO^-)Cbi remains unreacted. ATZ complexation with (H₂O)(HO^-)Cbi proceeds rapidly, i.e. rate constants for binding of the first and second ATZ molecules are (4.3 ± 0.5)×10³ and (5.8 ± 0.4)×10² M⁻¹ s⁻¹ (pH 7.4, 25.0 °C), respectively. The addition of ATZ to (H₂O)(HO^-)Cbi notably decreases the extent of Cbi species complexation with bovine serum albumin and the rate of Cbi(III) species reduction to Cbi(II) by glutathione, whereas the rates of reactions with cyanide and hydrogen sulfide remain relatively high. Thus, ATZ may prevent (H₂O)(HO^-)Cbi retention by proteins and its involvement in side redox reactions upon introduction in the human body, which explains the high absorption of the Cbi-ATZ complex during intramuscular injection and its high efficacy as an antidote.

Keywords:

• Cobinamide
• antidotes
• 5-aminoterazole
• bovine serum albumin

Disclosure statement

The authors declare no competing financial interests.

Additional information

Funding

This work was supported by the Russian Science Foundation (project no. 21-73-10057) to IAD. The study was carried out using the resources of the Center for Shared Use of Scientific Equipment of the ISUCT (with the support of the Ministry of Science and Higher Education of Russia, grant No. 075-15-2021-671).