^ many related compounds substitutued THIQs seem to have a sedative type of profile...not sure how the 6-MeO changes things
many also seem to antagonize dopaminergic pathways, inclusing the simple 1,2,3,4-THIQ and are proneurotoxins
Previous work has established that 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1-BnTIQ) causes a parkinsonian syndrome in rats
Culture with 100 μM 1-benzyl-1,2,3,4-tetrahydroisoquinoline for 24 h irreversibly reduced the dopamine content.
the 1-methyl analogue seems to be neuroprotective though
The endogenous amine 1-methyl-1,2,3,4- tetrahydroisoquinoline prevents the inhibition of complex I of the respiratory chain produced by MPP(+).
Author: Parrado, J : Absi, E : Ayala, A : Castano, A : Cano, J : Machado, A
Citation: J-Neurochem. 2000 Jul; 75(1): 65-71
Abstract: The endogenous monoamine 1-methyl-1,2,3,4-tetrahydroisoquinoline has been shown to prevent the neurotoxic effect of MPP(+) and other endogenous neurotoxins, which produce a parkinsonian-like syndrome in humans. We have tested its potential protective effect in vivo by measuring the protection of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the neurotoxicity elicited by MPP(+) in rat striatum by tyrosine hydroxylase immunocytochemistry. Because we know that cellular damage caused by MPP(+) is primarily the result of mitochondrial respiratory inhibition at the complex I level, we have extended the study further to understand this protective mechanism. We found that the inhibitory effect on the mitochondrial respiration rate induced by MPP(+) in isolated rat liver mitochondria and striatal synaptosomes was prevented by addition of 1-methyl-1,2,3,4-tetrahydroisoquinoline. This compound has no antioxidant capacity; therefore, this property is not involved in its protective effect. Thus, we postulate that the preventive effect that 1-methyl-1,2,3,4-tetrahydroisoquinoline has on mitochondrial inhibition for MPP(+) could be due to a "shielding effect," protecting the energetic machinery, thus preventing energetic failure. These results suggest that this endogenous amine may protect against the effect of several parkinsonism-inducing compounds that are associated with progressive impairment of the mitochondrial function
3.1.2 1,2,3,4-Tetrahydroisoquinolines
Yet another interesting framework that can be derived directly from the chemical structure of apomorphine is the 1,2,3,4-tetrahydroisoquinoline skeleton (THIQ, Figure 3.1, right). The
structure is frequently used in drugs interacting at a number of biological systems7,28,44,83,86,87.
Furthermore, its presence is abundant among various naturally occurring alkaloids42,75. In the
central nervous system, various endogenous and non-endogenous THIQs have been identified as
well, and often their presence is suggested to be related with Parkinson’s disease (e.g. Nmethylsalsolinol,
2)41,43,44,55,56,60,81,85, and alcohollism5,23,25,30,57,57,61,65. In many cases, these
derivatives are formed by the metabolism of dopamine and alcohol by in vivo Pictet-Spengler
cyclization reactions22,25,62,85. The neurotoxic effect of these compounds is closely related to that of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 3) due to MAO-A and MAO-B mediated
conversions of the THIQ moiety into a N-methylisoquinolinium ion (NMIQ+)34,52. As a result
analogous to MPP+, blockade of normal mitochondrial functioning by NMIQ+ causes cell death.
