Never heard of emraclidine
Yes, it’s interesting. Emraclidine is a positive allosteric modulator of the M4 acetylcholine receptor.
Quote from Wikipedia’s article about the receptor:
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine.
A quote from a 2021 review:
A role for the M4 mAChR is further supported by evidence from human clinical trials, where the M1/M4-preferring agonist, xanomeline, improved the positive, negative and cognitive symptoms in schizophrenic patients (Shekhar et al., 2008). While these results are encouraging, an unfavourable, peripheral side effect profile has prevented xanomeline progressing further into the clinic.
A further quote:
In 2018, Karuna therapeutics created ‘KarXT’, a combination therapy of xanomeline and trospium (a peripherally restricted mAChR antagonist) (Brannan et al., 2020). In KarXT, trospium specifically blocks the peripheral actions of xanomeline, while allowing xanomeline to provide therapeutic efficacy in the CNS. In phase IIb clinical trials, KarXT successfully reduced positive, negative and cognitive symptoms in schizophrenic patients, but some anti-muscarinic side effects such as constipation, nausea, dry mouth, dyspepsia and vomiting were still observed (Brannan et al., 2020).
Wow, this is news for me - from the same review article:
Muscarinic Receptor-Deficit Schizophrenia
Schizophrenia is a syndrome that is likely composed of multiple etiologies, but presents with similar symptoms. Thus, in the path forward for treatments, the syndrome should be broken up into distinct biological problems that can be solved with the correctly tailored treatment (Jablensky, 2006). [3H]-pirenzipine binding in human post-mortem brain slices identified a subset (∼25%) of schizophrenic patients that have a reduction of approximately 75% M1 mAChR expression in the Brodmann’s area nine of the pre-frontal cortex when compared to non-schizophrenic controls (Salah-Uddin et al., 2009; Scarr et al., 2009; Dean et al., 2016; Scarr et al., 2018). Patients with this reduced M1 mAChR expression profile have been classified as a distinct subset of patients with ‘muscarinic receptor-deficit syndrome’ (MRDS) schizophrenia. Gene expression microarray data indicate that 65 genes are distinctly altered in the MRDS group; these genes are important for controlling cell movement and cell signaling pathways, upstream of M1 mAChR (Scarr et al., 2018). This finding is important, because treatment of this subset of schizophrenic patients with M1 mAChR-selective ligands may fail. Indeed, in [3H]-N-methyl-scopolamine binding experiments using post-mortem brain tissues from MRDS and non-schizophrenics, an M1 mAChR-selective ligand, benzyl quinolone carboxylic acid (BQCA), had much weaker effects in the MRDS tissues than in the non-schizophrenic control tissues (Dean et al., 2016; Hopper et al., 2019). Thus, targeting an alternative receptor, such as the M4 mAChR, may be more beneficial for this subgroup of schizophrenic patients.
I am not sure the chart mentioned Sunovion (ulotaront) or Karuna (KarXT) .
Good to read that karxt was good for negatives and cognitive symptoms. I would lkke to try it out when it comes out.
I was talking to someone on reddit who told me they tried karxt by creating a fake company and then was able to purchase it. He said it made him nauseous so he stopped taking it.