Neurotoxins/neurotoxicity lead compounds

Neurotoxic chemicals enter the body via inhalation, ingestion, and/or dermal absorption. These chemicals and their metabolites enter the bloodstream and are partitioned from there into body tissues. Many neurotoxins are lipophiles and accumulate in adipose tissue. The brain is particularly vulnerable to lipophilic chemical attack since 50% of the dry weight of the brain is lipid, compared to 6-20% lipid makeup for other body organs. Not all neurotoxins, however, are lipophiles. Lead compounds, for example, that are hydrophilic are potent neurotoxins. 

Compound 79 is structurally related to TIQ 80, obtained on condensation of norepinephrine with formaldehyde (164), and to TIQ 81, detected in animal tissues after exposure to acetaldehyde (165). Acid-catalyzed dehydration of TIQ 82, the N-methyl analog of TIQ 79, should lead to the iminium species 83 (166), which on two-electron oxidation or by disproportionation should give the isoquinolinium salt 84. Such reactions, if occurring in vivo, would parallel similar reactions seen with the neurotoxin MPTP in its conversions to MPDP and MPP (167) and could possibly explain the neurotoxic effects seen with 117 (168). 

---