Chemistry:Robalzotan

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Robalzotan (INN, BAN; developmental code names NAD-299 and AZD-7371) is a selective serotonin 5-HT1A receptor antagonist which was under development for the treatment of major depressive disorder, anxiety disorders, gastrointestinal disorders, irritable bowel syndrome (IBS), and overactive bladder but was never marketed.[1][2][3][4][5]

It shows high affinity for the serotonin 5-HT1A receptor (Ki = 0.24–0.6 nM) and more than 500-fold selectivity for this receptor over other serotonin receptors.[2] The drug was shown to completely reverse the autoreceptor-mediated inhibition of serotonin release induced by the administration of selective serotonin reuptake inhibitors (SSRIs) like citalopram in rodent studies.[6] It produces hyperlocomotion in rodents at high doses.[2] The elimination half-life of robalzotan in humans is short at approximately 1.5 hours.[5] The drug achieved 62 to 85% occupancy of the serotonin 5-HT1A receptor at the time of peak concentrations in humans as measured with positron emission tomography (PET) imaging.[5]

Robalzotan was investigated by AstraZeneca as a potential antidepressant, but like many other serotonin 5-HT1A receptor modulators, was discontinued.[7] Later on, it was also researched for other indications, such as IBS, but was dropped once again due to lack of effectiveness[3] as well as a poor tolerability profile, which included effects such as "hallucinations or hallucination-like adverse events".[8]

Other serotonin 5-HT1A receptor antagonists such as (S)-UH-301 and WAY-100635 have notably been found to produce the head-twitch response, a behavioral proxy of psychedelic effects, in rodents, with this effect mediated by disinhibition of serotonin release and consequent indirect activation of serotonin 5-HT2A receptors.[9][10][11] In addition, the serotonin 5-HT1A receptor agonist buspirone markedly suppresses the hallucinogenic effects of psilocybin in humans, whereas the serotonin 5-HT1A receptor antagonist pindolol moderately potentiates the psychedelic effects of dimethyltryptamine (DMT) in humans.[12][13][14]

See also

References

  1. ↑ "Robalzotan - AdisInsight". https://adisinsight.springer.com/drugs/800006370. 
  2. ↑ 2.0 2.1 2.2 "Robalzotan (NAD‐299), a Novel Selective 5‐HT 1A Receptor Antagonist". CNS Drug Reviews 5 (3): 213–232. 1999. doi:10.1111/j.1527-3458.1999.tb00101.x. ISSN 1080-563X. 
  3. ↑ 3.0 3.1 "Developing Serotonergic Antidepressants Acting on More Than the Serotonin Transporter". Methods and Principles in Medicinal Chemistry. Wiley. 21 November 2017. pp. 335–367. doi:10.1002/9783527674381.ch12. ISBN 978-3-527-33538-1. "Several selective 5-HT1A receptor antagonists have also been synthesized and tested in the clinic [15]. Robalzotan (NAD-299 or AZD 7371) is a 5-HT1A receptor antagonist with over approximately 250-fold greater selectivity at this site compared with other serotonergic and non-serotonergic receptors [100]. Informing phase 2 dose selection, a PET neuroimaging study demonstrated that a single 10 mg oral dose appeared to occupy ∼62–85% and 68–75% of midbrain dorsal raphe and cortical 5-HT1A receptors [101]. Robalzotan monotherapy (5, 10, and 20 mg bid) was tested in 385 patients with MDD in a randomized, double-blind, placebo-controlled, paroxetine-controlled study [102]. Robalzotan did not possess antidepressant activity in this study, even for a post hoc test in those centers demonstrating a 2-point improvement on the HAMD scale for paroxetine compared with placebo (Tables 12.1 and 12.2)." 
  4. ↑ "Receptor binding characteristics of [3H]NAD-299, a new selective 5-HT1A receptor antagonist.". European Journal of Pharmacology 360 (2–3): 219–225. 1998. doi:10.1016/S0014-2999(98)00667-0. PMID 9851589. 
  5. ↑ 5.0 5.1 5.2 "Positron emission tomographic analysis of dose-dependent NAD-299 binding to 5-hydroxytryptamine-1A receptors in the human brain". Psychopharmacology (Berl) 167 (1): 37–45. April 2003. doi:10.1007/s00213-002-1355-0. PMID 12632244. 
  6. ↑ "The 5-HT(1A) receptor antagonist robalzotan completely reverses citalopram-induced inhibition of serotonergic cell firing.". European Journal of Pharmacology 382 (2): 133–138. 1999. doi:10.1016/S0014-2999(99)00592-0. PMID 10528148. 
  7. ↑ "Robalzotan AstraZeneca". Current Opinion in Investigational Drugs (London) 1 (2): 236–240. October 2000. PMID 11249580. 
  8. ↑ "Randomized, double-blind, placebo-controlled trial of the 5-HT1A receptor antagonist AZD7371 tartrate monohydrate (robalzotan tartrate monohydrate) in patients with irritable bowel syndrome". The American Journal of Gastroenterology 103 (10): 2562–2569. October 2008. doi:10.1111/j.1572-0241.2008.02115.x. PMID 18775020. "Hallucinations or hallucination-like AEs were reported by eight patients taking AZD7371, and by none of the patients in the placebo group. After these events led to discontinuation in six patients, the study was prematurely terminated. [...] A total of eight patients reported hallucinations or hallucination-like AEs (visual hallucination, auditory hallucination, or formication), [...] the reported occurrence of hallucinations in this trial adds to the mounting evidence that 5-HT1A receptors may have a role in disturbances of thinking. [...] It is possible that the reported hallucinatory effects in the trial resulted from an interaction with SSRIs. 5-HT1A receptors have previously been shown to have a modulatory effect on SSRI action. For example, the 5-HT1A receptor antagonist action of pindolol is thought to explain how this compound accelerates the onset of the antidepressant effect of SSRIs (28). A large number of patients in the present study were receiving SSRI antidepressants, and all but one of the AZD7371-treated patients who experienced hallucinations or hallucination-like AEs were receiving concomitant SSRI therapy. [...] Hallucinations have also been associated with the administration of AZD7371 20 mg b.i.d. or 20 mg once daily (o.d.) without prior dose titration in a phase I study initiated while the current study was in progress. Of the 12 healthy subjects who received AZD7371 (either 20 mg b.i.d. or 20 mg o.d.), 11 reported CNS-related AEs and 2 reported auditory hallucinations. [...] None of the subjects were taking any concomitant medications. The exact mechanism of hallucinations associated with AZD7371, therefore, remains unclear. [...] In conclusion, the clinical development of AZD7371 has been stopped, based on the early termination of this study due to the reported hallucinations and hallucination-like events in patients treated with AZD7371, [...]". 
  9. ↑ "Animal Models and Hallucinogenic Drugs". The Neuroscience of Hallucinations. New York, NY: Springer New York. 2013. pp. 253–277. doi:10.1007/978-1-4614-4121-2_14. ISBN 978-1-4614-4120-5. "Further research demonstrated that some non-hallucinogenic compounds also evoke headtwitches in mice. These include 5-HT1A antagonists S-(−)-UH 301 and WAY100635 (Darmani and Reeves 1996; Darmani 1998), [...] In the case of benzodiazepines and 5-HT1A antagonists, the effect was also mediated by 5HT2-receptors. While for 5HT1A antagonists the effect was indirect, [...] It has also been shown that the 5-HT1A receptor has a modulatory role in the behavioral effects of LSD using drug discrimination behavior models (Reissig et al. 2005; Marona-Lewicka and Nichols 1995)." 
  10. ↑ "The silent and selective 5-HT1A antagonist, WAY 100635, produces via an indirect mechanism, a 5-HT2A receptor-mediated behaviour in mice during the day but not at night. Short communication". Journal of Neural Transmission (Vienna) 105 (6–7): 635–643. 1998. doi:10.1007/s007020050085. PMID 9826108. 
  11. ↑ "[On the Functional Cross-Talk between Brain 5-HT1A and 5-HT2A Receptors"] (in Russian). Zhurnal Vysshei Nervnoi Deiatelnosti Imeni I P Pavlova 65 (2): 240–247. 2015. PMID 26080602. https://www.researchgate.net/profile/Elena-Kondaurova/publication/278794834_On_the_Functional_Cross-Talk_between_Brain_5-HT1A_and_5-HT2A_Receptors/links/5698685d08ae1c42790556e8/On-the-Functional-Cross-Talk-between-Brain-5-HT1A-and-5-HT2A-Receptors.pdf. 
  12. ↑ "Drug-drug interactions involving classic psychedelics: A systematic review". Journal of Psychopharmacology (Oxford, England) 38 (1): 3–18. January 2024. doi:10.1177/02698811231211219. PMID 37982394. 
  13. ↑ "Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience". European Neuropsychopharmacology 26 (4): 756–766. April 2016. doi:10.1016/j.euroneuro.2016.01.005. PMID 26875114. 
  14. ↑ "5-HT1A receptor blockade potentiates the subjective effects of DMT". Journal of Psychopharmacology (Oxford, England). May 2026. doi:10.1177/02698811261443696. PMID 42068196. 



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