Pharmacological profile of antidepressants and related compounds at human monoamine transporters
Introduction
After the early work of Kuhn (1958), researchers discovered that most antidepressants were inhibitors of transporters for serotonin and norepinephrine in the presynaptic nerve ending (Glowinski and Axelrod, 1964; Ross and Renyi, 1969). Although blockade by antidepressants of biogenic amine uptake into nerve endings is one of the cornerstones of the biogenic amine hypothesis of affective illness (Maas, 1975), the exact mechanism of action of antidepressants in alleviating depression remains uncertain. Nonetheless, this property of antidepressants clearly relates to some of their adverse effects and some of their drug–drug interactions (Richelson, 1994).
Re-uptake of serotonin, norepinephrine, and dopamine into nerve endings is a process that prevents overstimulation of receptors in the synapse. This process of re-uptake occurs through the action of unique proteins that have been molecularly cloned from several species, including human (Pacholczyk et al., 1991; Ramamoorthy et al., 1993; Pristupa et al., 1994; Eshleman et al., 1995).
We (Richelson and Pfenning, 1984; Bolden-Watson and Richelson, 1993) and many others (e.g., see Koe, 1976; Shank et al., 1987) have obtained data for the inhibitory potency of antidepressants at blocking re-uptake into rat brain synaptosomal preparations. However, with numerous examples in the literature of species differences for binding of compounds to molecularly cloned proteins, including the serotonin transporter (Barker et al., 1994; Barker and Blakely, 1996), we were interested to determine the binding potencies of antidepressants and related compounds for the human serotonin, norepinephrine, and dopamine transporters and to compare these data with our previously obtained data using rat brain synaptosomal preparations. The results, which include some interesting differences from our previous data (Richelson and Pfenning, 1984; Bolden-Watson and Richelson, 1993), are presented here.
Section snippets
Materials
The following drugs were generously provided by the manufactures: alprazolam from Upjohn Co. (Kalamazoo, MI); butriptyline from Ayerst Laboratories (New York, NY); carbamazepine, oxaprotiline from CIBA Pharmaceuticals (Summit, NJ); citalopram, desmethylcitalopram from Lundbeck and Co. (Kobenhaun, Denmark); desmethylsertraline maleate, doxepin HCl, and sertraline HCl from Pfizer Central Research (Groton, CT); dothiepin from Marion Laboratories (Kansas City, MO); etoperidone HCl from Angelini
Results
The data are summarized in Table 1Table 2. The KD's for antidepressants and related compounds in this study were derived from competition experiments with varying concentrations of the compounds. Hill coefficients (nH's) for all of the compounds at each binding site were close to unity (data not shown), suggesting that the binding of the drugs in the radioligand binding assay obeyed the law of mass action.
For imipramine the KD and nH were 1.40±0.03 nM and 0.980±0.004 (n=51), respectively; for
Discussion
This study reports the binding potencies of 37 antidepressants, three metabolites of antidepressants, some mood stabilizers including antiepileptic drugs, two Ca2+ channel antagonists, two hormones, two benzodiazepines, some psychostimulants, antihistamines, and other monoamines for the human serotonin, norepinephrine and dopamine transporters.
Our KD value for imipramine (KD=1.40 nM) was similar to that of a high-affinity binding site (KD=1.2 nM) reported by Brust et al. (1995)and the value (KD
Acknowledgements
This work is supported by Mayo Foundation for Medical Education and Research and USPHS grant MH27692 from N.I.M.H. We thank Dr. Zdenek B. Pristupa and Dr. H.B. Niznik, University of Toronto for supplying a cDNA encoding the human dopamine transporter.
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