Editing Openai/68f254dc-1570-8004-ab56-efe884c7e623 (section)

==== ⚗️ What changes with 6-methyl-nicotine (6-MN)? ====

===== 1. Same enzymes, different affinity =====

Experimental and computational docking data (from Philip Morris CR-1542, Battelle 1960s, and later in silico CYP2A6 models) show:
* 6-MN still fits the CYP2A6 active site but with ~40–60% lower binding affinity for the 5′-oxidation site.
* The methyl group at C-6 creates steric hindrance that alters orientation in the enzyme pocket, reducing formation of the iminium intermediate that yields cotinine.

➡️ Result:
Metabolism through the main nicotine → cotinine route is slower or less efficient.

===== 2. Reduced conversion to cotinine =====
* In vitro rat and microsomal studies (e.g., PM Science CR-1437, 1973) found less cotinine formed from 6-MN compared to nicotine — roughly ⅓ to ½ the amount over equal incubation times.
* Some alternative oxidation sites appear (e.g., hydroxylation on the methyl substituent), leading to 6-hydroxymethyl-nicotine or 6-methyl-cotinine–like analogs.
* These are minor and not well characterized pharmacodynamically (we don’t know if they bind nicotinic receptors or have activity like cotinine).

➡️ So, while the types of metabolism (oxidation, N-oxidation, conjugation) are conserved, the quantitative branching ratios differ.

===== 3. Likely slower clearance and longer plasma half-life =====

Because 6-MN:
* Is more lipophilic (slower renal excretion, greater tissue distribution)
* Has reduced CYP2A6 catalytic efficiency (slower oxidative turnover)

→ Predicted half-life is 1.5–3× that of nicotine, so perhaps 4–6 hours instead of 1–2.
This aligns with anecdotal reports and old pharmacology data suggesting 6-MN produces a longer but smoother nicotinic effect.

===== 4. Potentially reduced formation of reactive intermediates =====

The iminium intermediate from nicotine metabolism (especially under oxidative stress) can yield reactive aldehydes that damage proteins/DNA.
Because 6-MN forms less of that intermediate, its oxidative metabolite load might be lower, theoretically implying less hepatotoxicity and oxidative stress.