Chemistry and Pharmacology of Nicotinic Ligands Based on 6‐[5‐(Azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol (AMOP‐H‐OH) for Possible Use in Depression
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AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4) 3 (β2) 2 ‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.
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Both varenicline and sazetidine-A have shown antidepressant efficacy in the forced swim test.
“both varenicline and sazetidine-A have shown antidepres- sant efficacy in the forced swim test (Caldarone et al, 2011; Kozikowski et al, 2009; Mineur et al, 2011; Rollema et al, 2009; Turner et al, 2010).”
From Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal (2013) · cites this paper as Kozikowski et al, 2009
In preclinical tests, saz-A produces behavior indicative of potential antidepressant and/or antianxiety effects.
“in preclinical tests saz-A produces behavior indicative of potential antidepressant and/or antianxiety effects (Kozikowski et al., 2009;Turner et al., 2010Turner et al., , 2011;;Caldarone et al., 2011).”
From Chronic Sazetidine-A at Behaviorally Active Doses Does Not Increase Nicotinic Cholinergic Receptors in Rodent Brain (2012) · cites this paper as Kozikowski et al., 2009
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- Authors
- Kozikowski, A. P., Eaton, J. B., Bajjuri, K. M., Chellappan, S. K., Chen, Y., Karadi, S., He, R., Caldarone, B., Manzano, M., Yuen, P., & Lukas, R. J.
- Affiliations
- University of Illinois Chicago (US)
- Barrow Neurological Institute (US)
- Psychogenics (United States) (US)
- Corresponding author
- Lukas, Ronald J.
- Venue
- ChemMedChem
- Publisher
- Wiley
- Published
- 2009-07-30
- Volume
- 4
- Issue
- 8
- Pages
- 1279-1291
- ISSN
- 1860-7179 (ISSN-L)
- 1860-7187
- PMC
- PMC2955514
- OpenAlex
- W1981086691
- Cited by
- 36
- References
- 31
- Citations by year
- 2020: 1 · 2018: 1 · 2016: 4 · 2015: 2 · 2014: 5 · 2013: 8 · 2012: 7
- FWCI
- 2.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ChemMedChem (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01DA015389, R01DA017980)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Alkaloids: synthesis and pharmacology
- Keywords
- nicotinic acetylcholine receptors, alpha4beta2 nAChR, antidepressant effects, partial agonism, receptor desensitization, receptor antagonism, forced swim test, nicotine dependence
- MeSH terms
- Animals, Antidepressive Agents, Azetidines, Depression, Humans, Ligands, Motor Activity, Pyridines, Receptors, Nicotinic, Protein Isoforms, Mice
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