atara
Bluelighter
Piperazines suck. But why? Often we have blamed 5-ht2c.
"TFMPP has affinity for the 5-HT1A (Ki = 288 nM), 5-HT1B (Ki = 132 nM), 5-HT1D (Ki = 282 nM), 5-HT2A (Ki = 269 nM), and 5-HT2C (Ki = 62 nM) receptors, and functions as a full agonist at all sites except the 5-HT2A receptor "
But there is another receptor here which is not normally a primary target of psychedelics.
"In the frontal cortex, it is believed to act as a postsynaptic receptor inhibiting the release of dopamine. In the basal ganglia and the striatum, evidence suggests 5-HT signaling acts on an autoreceptor, inhibiting the release of serotonin[9] and decreasing glutamatergic transmission by reducing miniature excitatory postsynaptic potential (mEPSP) frequency,[10] respectively. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression.[11] When the expression of 5-HT1B in human cortex was traced throughout life, significant changes during adolescence were observed, in a way that is strongly correlated with the expression of 5-HT1E.[12]
Outside the brain, 5-HT1B receptor activation also has vascular effects, such as pulmonary vasoconstriction."
Notably, while LSD binds to a lot of serotonin receptors, it avoids this one, although it still binds 5-ht2c:
en.wikipedia.org
edit: apparently the piperazines are all potent broad-spectrum CYP inhibitors, and while I don't know if that could have any effect on their psychological profile it means that the class is not worth exploring even if there are variants with good serotonin activity (while it won't cause nausea by itself, it could easily cause nausea if you have taken or eaten ~anything weird)
"TFMPP has affinity for the 5-HT1A (Ki = 288 nM), 5-HT1B (Ki = 132 nM), 5-HT1D (Ki = 282 nM), 5-HT2A (Ki = 269 nM), and 5-HT2C (Ki = 62 nM) receptors, and functions as a full agonist at all sites except the 5-HT2A receptor "
But there is another receptor here which is not normally a primary target of psychedelics.
"In the frontal cortex, it is believed to act as a postsynaptic receptor inhibiting the release of dopamine. In the basal ganglia and the striatum, evidence suggests 5-HT signaling acts on an autoreceptor, inhibiting the release of serotonin[9] and decreasing glutamatergic transmission by reducing miniature excitatory postsynaptic potential (mEPSP) frequency,[10] respectively. In the hippocampus, a recent study has demonstrated that activation of postsynaptic 5-HT1B heteroreceptors produces a facilitation in excitatory synaptic transmission which is altered in depression.[11] When the expression of 5-HT1B in human cortex was traced throughout life, significant changes during adolescence were observed, in a way that is strongly correlated with the expression of 5-HT1E.[12]
Outside the brain, 5-HT1B receptor activation also has vascular effects, such as pulmonary vasoconstriction."
Notably, while LSD binds to a lot of serotonin receptors, it avoids this one, although it still binds 5-ht2c:
LSD - Wikipedia
edit: apparently the piperazines are all potent broad-spectrum CYP inhibitors, and while I don't know if that could have any effect on their psychological profile it means that the class is not worth exploring even if there are variants with good serotonin activity (while it won't cause nausea by itself, it could easily cause nausea if you have taken or eaten ~anything weird)
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