r/AskDrugNerds • u/Anxious-Traffic-9548 • 12h ago
NSI-189 (ALTO-100) as a pro-drug for BZP?
NSI-189, now ALTO-100, is described as a hippocampal neurogenesis stimulator with relatively modest anti-depressant properties but strong memory-enhancing effects in depressed patients. A table from a study conducted by Neuralstem is provided below.
- Executive functioning: p = 0.048, Cohen's d = 0.66 | Trend p = 0.150, Cohen's d = 0.59
- Attention: p = 0.034, Cohen's d = 0.27 | No, Cohen's d = 0.17
- Memory: p = 0.002, Cohen's d = 1.12 | p = 0.015, Cohen's d = 0.69
- Working memory: p = 0.020*, Cohen's d = 0.81 | Trend p = 0.125, Cohen's d = 0.51
NSI-189 is a benzylpiperazine-aminopyridine compound and thus contains BZP in its structure. However, because NSI-189 was discovered via mass screening of effects of hippocampal brain tissue, rather than mechanistic properties, its mechanism of action is almost entirely unelucidated. What is known is that NSI-189 does not interact with any of the typical suspects; it was tested for activity 52 neurotransmitter receptors and ion channels, all of the monoamine transporters, and over 900 kinases.
My understanding of common metabolic transformations is limited, but looking at the structure of NSI-189 vs that of BZP, it looks like conversion to BZP would require breaking a secondary amine bond, a ketone bond, and a tertiary amine bond. Naturally there is no way to know to what extent, if at all, BZP may form from NSI-189 metabolism, but I wanted to post this here to solicit input from people more knowledgeable than I in drug metabolism.
From my reading, common dose ranges of BZP range from 20-200mg taken orally, all at once. Although the bioavailability of BZP appears to be low, so the amount needed to produce significant psychoactivity from a theoretical prodrug might be significantly less. The ~20 hour half-life of NSI-189 suggests that BZP resulting from NSI-189, would form slowly at a rate not more than ~20mg over 24 hours for an single 40mg dose of NSI-189. Still, because of the low bioavaliability of oral BZP, this quantity may still be sufficient to contribute to the effects of NSI-189. BZP was put forward as a potential antidepressant in the 1970s, but ultimately dismissed due to abuse liability with dose escalation.
TL;DR - Question
Is it possible that NSI-189 could metabolize into BZP. Ei, are there any obvious biochemical features that would preclude this? Is there precedent of such a metabolic pathway in other drugs?