Pharmacology Nicotine derivatives

[red22]

Do any of these things have any psychoactive value? I found this …

"I made 6-chloronicotine once, Chichibabin on nicotine, separate regioisomers, then Sandmeyer on the product. I’d got into the terrible habit of sniffing a flask after rotary evaporation to check for residual solvent. The whiff of 6-chloronicotine almost made me pass out, I was grasping at the hood trying to stay upright. Additionally it was Saturday and I was in the lab alone. Later I checked, and this is a known compound which is 10x more toxic than nicotine. Pretty toxic stuff. I was stupid but lucky." Android109, h‍ttps://www.reddit.com/r/chemistry/comments/103p2qf/comment/j31gz8a/

6-Chloronicotine - Wikipedia

en.wikipedia.org

I asked about making nicotine more amphetamine-like, since it's quite weak and short-lived. This is what Claude said:

As for an amphetamine-like nicotinic compound — the honest answer is that the receptor pharmacology works against you. Amphetamine's euphoric/stimulant profile comes primarily from monoamine reuptake inhibition and reversal (dopamine, norepinephrine). nAChR agonism does release dopamine, but indirectly and more diffusely. The two mechanisms are quite different in character.

To get true amphetamine-like effects from a nicotine scaffold you'd probably need to graft on monoaminergic activity, at which point you've essentially built a hybrid molecule that isn't really "nicotine-derived" in any meaningful pharmacological sense anymore.

The closest thing might actually be epibatidine — a frog-derived nAChR agonist of extraordinary potency — but its therapeutic index makes 6-chloronicotine look safe by comparison.

 

[tuppingtoncity]

I’ve certainly been wondering about the pharmacology / subjective experience of long(er) lasting nicotine analogues, however like you mentioned they don’t seem particularly viable. Would love to hear if someone knows more about this topic

 

[red22]

Links from ChatGPT:

Levels of the nicotine analog 6-methyl nicotine as a naturally formed tobacco alkaloid in tobacco and tobacco products

Synthetic nicotine analogues to evade rules? The case of 6-methylnicotine

Introduction of nicotine analogue-containing oral pouch products in the United States

Nicotine Analogues in Oral Pouch Products and Associated Marketing Claims

Novel E-Cigarette Products Marketed to Contain Nicotine Analogs Instead of Nicotine Show Discrepancies Between Label Information and Contents

High Variability in Nicotine Analog Contents, Misleading Labeling, and Artificial Sweetener in New E-Cigarette Products Marketed as “FDA-Exempt”

Machine Learning Neuroprotective Strategy Reveals a Unique Set of Parkinson Therapeutic Nicotine Analogs

An electrophysiological characterization of naturally occurring tobacco alkaloids and their action on human α4β2 and α7 nicotinic acetylcholine receptors

Minimal Structural Changes Determine Full and Partial Nicotinic Receptor Agonist Activity for Nicotine Analogues

Synthesis, nicotinic acetylcholine receptor binding, in vitro and in vivo pharmacology properties of 3′-(substituted pyridinyl)-deschloroepibatidine analogs

Synthesis, Nicotinic Acetylcholine Receptor Binding, and Antinociceptive Properties of 2′-Fluoro-3′-(substituted pyridinyl)-7-deschloroepibatidine Analogues

Synthesis and activity of substituted heteroaromatics as positive allosteric modulators for α4β2α5 nicotinic acetylcholine receptors

Insecticidal activity and mode of action of novel nicotinoids synthesized by new acylpyridinium salt chemistry and directed lithiation

5-Substituted, 6-Substituted, and Unsubstituted 3-Heteroaromatic Pyridine Analogues of Nicotine as Selective Inhibitors of Cytochrome P-450 2A6

Pyrrolidine-modified and 6-substituted analogs of nicotine: A structure—affinity investigation

And one that I found:

Regioselective C-2 and C-6 Substitution of (S)-Nicotine and Nicotine Derivatives


"Nicotine treats ADHD. In fact, we have 3 drug companies now exploring variations of the nicotine molecule. The problem? When they split off the addictive part, they often lose the therapeutic benefit too." Dr. Russell Barkley, h‍ttps://x.com/newstart_2024/status/2020617250391072949 2026-02-08

 

[red22]

Talk of nicotine analogs here, post-16234280, and in below posts.

 

[MedicinalUser247]

Here's a Nicotine analog. I call it Trifluoronicorex. https://ibb.co/JWG9PLq2

 

[red22]

And one that I found:

Regioselective C-2 and C-6 Substitution of (S)-Nicotine and Nicotine Derivatives

I had Claude read that article. It said one of the articles it referenced would be better for my inquiry:

Neuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discovery. Holladay, Mark W., Dart, Michael J., Lynch, John K. 1997. Journal of Medicinal Chemistry, 40(26), 4169–4194. 10.1021/jm970377o

This was Claude's response to this article:

Psychoactive effects of nicotine derivatives — what Holladay et al. actually say

On dopamine specifically

The paper addresses this directly. Several nicotine derivatives show distinct dopamine release profiles compared to nicotine itself. A key finding is that DA release from rat striatum and α4β2 activation are dissociable — compounds can differ substantially in their relative potency at these two systems. For example, SIB-1765F stimulates DA release with greater efficacy than nicotine but with much lower potency, and shows less efficacy than nicotine at human recombinant α4β2. ABT-089 is a partial agonist (~70% of nicotine) for DA release but shows low efficacy at recombinant α4β2 and ganglionic receptors. This suggests the receptor subtype mediating striatal DA release is likely not simply α4β2 but involves additional subtypes, possibly α6-containing receptors (discussed in the n-Bgt-sensitive subtype section).

Importantly, cytisine — a partial agonist — is potent at stimulating DA release in rat despite being only a weak activator of rat α4β2. This partial agonism at DA-release receptors is pharmacologically significant: it is the same mechanism that varenicline later exploited clinically.

On duration of action

The paper doesn't directly discuss pharmacokinetics, but it does note that ABT-089's secondary amine (vs. nicotine's N-methyl tertiary amine) enhances oral bioavailability, possibly by improving metabolic stability to liver enzymes. This is a direct structural observation relevant to duration — desmethylation at the pyrrolidine nitrogen slows CYP2A6 metabolism. For the C-6 and C-2 substituted derivatives from the Février paper, the same logic would plausibly apply to electron-withdrawing substituents slowing oxidative metabolism.

On subtype selectivity and side effects

The paper is very explicit that the goal of the whole field is to separate α4β2 CNS effects from α3β4 ganglionic effects (cardiovascular, GI) and from muscle-type nAChRs (neuromuscular). ABT-418, RJR-2403, and A-84543 each show modest improvements in this selectivity over nicotine. Strikingly, for RJR-2403 analogues, a methyl group at the 6-position of the pyridine ring — directly analogous to one of the substitution positions in the Février paper — actually increases potency for DA release (EC50 drops from 1470 nM to 219 nM) while reducing α4β2 binding affinity. This is a direct and highly relevant data point connecting the Février chemistry to pharmacological outcomes.

On abuse potential and cognition

The paper notes α4β2 upregulation as a unique feature of chronic nicotine exposure, and ties this to both tolerance and, implicitly, dependence. Partial agonists that cause less desensitization or upregulation would theoretically carry lower abuse liability — again the varenicline principle, foreshadowed here.

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In short, this paper provides strong grounds for inferring that C-6 substituted nicotines from the Février paper — particularly those with electron-withdrawing groups or methyl substituents at C-6 — could meaningfully alter DA release potency and subtype selectivity, with real consequences for both therapeutic potential and side effect profile.

 

[MedicinalUser247]

This is what I read. "Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-α-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (−)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 μM, respectively. Such stimulation was sensitive to mecamylamine and DHβE. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1765F was less efficacious than (−)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (−)-nicotine. Similar to (−)-nicotine and (±)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (−)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for hα4β2 NAChR relative to hα4β4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic Ca++ concentration in cell lines stably expressing hα4β2 or hα4β4."

 

[MedicinalUser247]

Here's another Nicotine analog. I call it Rush. https://ibb.co/q3cNVb1J

 

[Smyth2]

This analog of varenicline is called CP-601927.

Coe, Jotham W.; Brooks, Paige R.; Wirtz, Michael C.; Bashore, Crystal G.; Bianco, Krista E.; Vetelino, Michael G.; Arnold, Eric P.; Lebel, Lorraine A.; Fox, Carol B.; Tingley, F. David; Schulz, David W.; Davis, Thomas I.; Sands, Steven B.; Mansbach, Robert S.; Rollema, Hans; O’Neill, Brian T. (2005). "3,5-Bicyclic aryl piperidines: A novel class of α4β2 neuronal nicotinic receptor partial agonists for smoking cessation". Bioorganic & Medicinal Chemistry Letters. 15 (22): 4889–4897. doi:10.1016/j.bmcl.2005.08.035.

 

[MedicinalUser247]

What would be a Nicotinic Full-Agonist ?

 

[MedicinalUser247]

Have you ever Heard of 6-Phospho-Nicotine ? https://ibb.co/bMRzWnj1