Lysergamides LSD prodrugs and potency

[iom]

I've always been curious as to what 5-HT2c contributes to the psychedelic experience with different drugs. Unlike 5-HT2a and 5-HT2b which are expressed throughout the body, I believe 5-HT2c is only expressed in the brain. I understand at least one possible function of 5-HT2c is to modulate dopamine transmission. From data I've seen, it appears that most psychedelic drugs that people enjoy taking have less affinity at 5-HT2c than 5-HT2a, generally. (Caveat: Testing different receptors means using different assays, and assays are notoriously inconsistent between each other---hence it can be difficult to compare affinities between receptor types if they are of similar order of magnitude.)

My views on these things are something like:
* 5-HT2a: essential for psychedelic effects
* 5-HT2b: important for entactogenic effects---may "soften" or "warm" the psychedelic effect by enhancing endogenous serotonin release
* 5-HT2c: ????? (side-effects? anorexia?)
* 5-HT1a: dampens or amplifies psychedelic effects (depending on degree of effect of the partial agonist). May play a role in ego loss type effects???
* alpha and beta adrenergic receptors: affects degree of arousal or stimuation during the experience---possibly establishing a floor and/or ceiling of arousal that arises during experience

Most psychedelics people like to use have high affinity at 5-HT2a and 5-HT2b. A few (like LSD and mescaline) have high affinity at 5-HT1a. Most also have significant affinity for at least one adrenergic receptor. Some have moderate affinity at 5-ht2c. I should mention that LSD and presumably other lysergamides also have some affinity for dopamine receptors, but not really any of the common non-lysergamides.

I've never personally had ALD-52, so I haven't the slightest idea of it feels different from LSD.

Fun fact: the 5-HT2c receptor is encoded in the DNA of the X chromosome, which means heritable differences are sex linked.

 

[4DQSAR]

Fun fact: the 5-HT2c receptor is encoded in the DNA of the X chromosome, which means heritable differences are sex linked.

...gender linked? Or do you mean doing the nasty?

 

[iom]

...gender linked? Or do you mean doing the nasty?

I prefer not to use the term "gender" in this context given today's cultural sensitivities around the concept and because this discussion has everything to do with the presence of XX versus XY chromosome pairs. In my old pre-"woke" biology textbook, sex-linked is the term used most frequently to describe phenotypical traits that arise from genes on the X chromosome.

 

[Allylbenzene]

...what 5-HT2c contributes to the psychedelic experience

This description of 5-HT2c antagonism is from a 2005 paper:

These observations underpin interest in 5-HT2C receptor blockade as a strategy for treating depressive and anxious states. This notion is supported by findings that 5-HT2C receptor antagonists stimulate dopaminergic and adrenergic pathways, exert antidepressant and anxiolytic actions in behavioural paradigms...

https://doi.org/10.2515/therapie:2005065

My views on these things are something like:
...
* alpha and beta adrenergic receptors: affects degree of arousal or stimuation during the experience

Alpha-2 adrenergic agonists are able to produce sedation, analgesia, euphoric effects and partially block acute withdrawal symptoms in chronic opioid users.

https://doi.org/10.2344/0003-3006-62.1.31)

LSD might interact with TAAR1 also, and let's not forget 5-HT6 and HT7:

Synaptogenic responses occur after agonism at additional receptor sites including 5-HT6 and 5-HT7. Since DMT can bind to these receptors, we speculate that its mechanism of action may include their diverse effects after activation. For example, the agonism of 5-HT7 facilitates synaptogenesis and increases the density of dendritic spines in the forebrains of mice. Chronic activation leads to sustained effects within the postnatal cortical and striatal neurons. Acute activation resulted in neurite elongation within these regions. This effect also occurs within the hippocampus at early postnatal stages. The 5-HT7 receptor also mediates arborization in rat forebrains due to agonism in late adolescent development, and is maintained into adulthood. This effect may occur in an age-dependent manner, with the structural effects being attenuated into adulthood.

Another target of interest includes the 5-HT6 receptor, which plays a role in the development of neural circuits. Specifically, its activation is implicated in neuronal migration and neurite outgrowth. Constitutive activation of 5-HT6 through its interaction with Cdk5 leads to neurite growth, which was abolished through the administration of a 5-HT6 receptor antagonist. These 5-HT6 receptor sites have received less attention as potential mediators of psychedelic-mediated neuritogenesis, and future investigation into their contribution is certainly warranted based on the preliminary findings of in vitro and in vivo studies.

https://doi.org/10.3390/psychoactives3010007

One of the primary outcomes of 5-HT7 activation is the modulation of neurotransmitter release. By influencing the release of other neurotransmitters such as glutamate, GABA and dopamine, 5-HT7 agonists can exert a wide range of effects on the nervous system.

• synapse.patsnap.com/article/what-are-5-ht7-receptor-agonists-and-how-do-they-work
• 10.1021/acschemneuro.8b00283

This review explores the individual roles of 5-HT1A and 5-HT7 receptors, as well as their coexpression, in memory regulation. The heterodimerization of these receptors at both pre- and postsynaptic levels, along with their colocalization in serotonergic, glutamatergic, GABAergic, and dopaminergic neurons, adds to the complexity of this interaction

https://doi.org/10.3390/biom15060762