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Neurotransmitter Receptor and Transporter Binding Profile of Antidepressants and Their Metabolites
Abstract
Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand binding assays, we measured the affinity (Ki) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The Ki values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha-1 and alpha-2 receptors. These data are useful for predicting side effect profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a "dual uptake inhibitor", possesses weak affinity for the NET. We observed significant correlations in SERT (r = 0.965) or NET (r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha-1 and alpha-2 receptors. These…
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Paroxetine has higher affinity for muscarinic acetylcholine receptors compared with other SSRIs.
“Paroxetine was found to have higher affinity for muscarinic acetylcholine receptors compared with other SSRIs (20,21).”
From Risk of Dementia Among Elderly Nursing Home Patients Using Paroxetine and Other Selective Serotonin Reuptake Inhibitors (2015) · cites this paper as [21]
Paroxetine has strong anticholinergic properties.
“Among the SSRIs, paroxetine has strong anticholinergic properties and may lead to increased risk of adverse cognitive outcomes among elderly patients.”
From Risk of Dementia Among Elderly Nursing Home Patients Using Paroxetine and Other Selective Serotonin Reuptake Inhibitors (2015) · cites this paper as [21]
Owen and others found that paroxetine's muscarinic binding was similar to that of desipramine but much lower compared with amitriptyline and substantially higher compared with sertraline.
“Owen and others (21) found that paroxetine's muscarinic binding was similar to that of desipramine but much lower compared with amitriptyline and substantially higher compared with sertraline.”
From Risk of Dementia Among Elderly Nursing Home Patients Using Paroxetine and Other Selective Serotonin Reuptake Inhibitors (2015) · cites this paper as [21]
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Metadata
- Authors
- Owens, M. J., Morgan, W. N., Plott, S. J., & Nemeroff, C. B.
- Affiliations
- Emory University (US)
- ORCID
- Nemeroff, Charles B.
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 1997-12
- Volume
- 283
- Issue
- 3
- Pages
- 1305-1322
- ISSN
- 0022-3565 (ISSN-L)
- OpenAlex
- W2167977201
- Cited by
- 676
- References
- 0
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 11 · 2023: 10 · 2022: 14 · 2021: 19 · 2020: 17 · 2019: 18 · 2018: 27 · 2017: 11 · 2016: 28 · 2015: 36 · 2014: 28 · 2013: 27 · 2012: 32
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- National Institute of Mental Health (R01MH040524)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- antidepressants, antidepressant metabolites, serotonin transporter, norepinephrine transporter, nefazodone, paroxetine, venlafaxine, 5-HT1A receptor, 5-HT2A receptor, muscarinic receptors, histamine H1 receptor, alpha1-adrenoceptors, alpha2-adrenoceptors, radioligand binding affinity, drug-drug interactions, side effect prediction, G protein-coupled receptors, transporter affinity
- MeSH terms
- Animals, Carrier Proteins, Chromatography, High Pressure Liquid, Guinea Pigs, Humans, Male, Membrane Glycoproteins, Nerve Tissue Proteins, Piperazines, Radioligand Assay, Receptors, Serotonin, Triazoles, Rats, Sprague-Dawley, Receptors, Neurotransmitter, Antidepressive Agents, Second-Generation, Membrane Transport Proteins, Symporters, Norepinephrine Plasma Membrane Transport Proteins, Serotonin Plasma Membrane Transport Proteins, Rats
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