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Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?​


Abstract​

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D(2) receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D(2) and 5-HT(2A) antagonists, and those that also bind with modest affinity to D(2), 5-HT(2A), and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D(2) partial agonism or D(2) functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D(2) functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D(2) antagonists.

good review about functional selectivity of newer antipsychotics.

pubmed.ncbi.nlm.nih.gov

Third generation antipsychotic drugs: partial agonism or receptor functional selectivity? - PubMed

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov
 
Carmen A Zavala, Ana C Thomaz, Vishakh Iyer, Ken Mackie, Andrea G Hohmann, Cannabinoid CB2 Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression, Cannabis Cannabinoid Res 2021 Oct;6(5):389-400.


pubmed.ncbi.nlm.nih.gov

Cannabinoid CB2 Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression - PubMed

<span><b>Introduction:</b> Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

There's no obvious way to modify the structure of any of the known selective CB2 agonists to also make them bind to the mu opioid receptor at the same time, but AM-1241 is one compound where this looks like it could be possible. One theoretically possible risk is that you could be even more prone to opioid respiratory depression than normal for some time after quitting chronic cannabinoid use.
 
On The Quest For Better Antibiotics: This Fairly Recent Article Indicates That The Major Component Of Grapefruit Essential Oil (EO) Is Limonene. The Antimicrobial Effects Of Various Chemical Compounds Found In The EO Of Grapefruit Are Discussed. This EO Has Also Been Shown To Potentiate Certain Drugs.

www.ncbi.nlm.nih.gov

Chemical Composition, Antimicrobial, Antioxidant, and Antiproliferative Properties of Grapefruit Essential Oil Prepared by Molecular Distillation

Grapefruit essential oil has been proven to have wide range of bioactivities. However, bioactivity of its molecular distillate has not been well studied. In this study, a light phase oil was obtained by molecular distillation from cold-pressed grapefruit ...
www.ncbi.nlm.nih.gov www.ncbi.nlm.nih.gov
 
These Product N-N's Are Going To Be Explosive, I Would Think.

www.nature.com

Organocatalytic diastereo- and atroposelective construction of N–N axially chiral pyrroles and indoles - Nature Communications

N–N axially chiral motifs are of synthetic interest due to their presence in natural products, pharmaceuticals, and chiral ligands. Here, the authors develop a direct catalytic synthesis of N–N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC...
www.nature.com www.nature.com
 
chemrxiv.org

Synthesis of N–H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent

Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with non-activated alkenes...
chemrxiv.org chemrxiv.org

I'm thinking once you have the N-H aziridine from the arene precursor, it could be opened somehow.
 
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