Abstract
Using radioligand binding assays and postmortem normal human brain tissue, we obtained equilibrium dissociation constants (Kds) for 17 antidepressants and two of their metabolites at histamine H1, muscarinic, α1-adrenergic, α2-adrenergic, dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but α2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at α2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H1 receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant.
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Bolden C, Cusack B, Richelson E (1992) Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells. J Pharmacol Exp Ther 260:576–580
Bolden-Watson C, Richelson E (1993) Blockade by newly-developed antidepressants of biogenic amine uptake into rat brain synaptosomes. Life Sci 52:1023–1029
Buckley NJ, Bonner TI, Buckley CM, Brann MR (1989) Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol 35:469–476
Bylund DB, Blaxall HS, Iversen LJ, Caron MG, Lefkowitz RJ, Lomasney JW (1992) Pharmacological characteristics of α2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol 42:1–5
Convents A, De Keyser J, De Backer JP, Vauquelin G (1989) [3H]Rauwolscine labels α2-adrenoceptors and 5-HT1A receptors in human cerebral cortex. Eur J Pharmacol 159:307–310
Cusack BM, Richelson E (1993) A method for radioligand binding assays using a robotic workstation. J Recept Res 13[1–4]: 123–134
De Lean A, Hancock AA, Lefkowitz RJ (1982) Validation and statistical analysis of a computer modelling method for quantitative analysis of radio-ligand binding data for mixtures of pharmacological receptor subtypes. Mol Pharmacol 21:5–16
De Vos H, Czerwiec E, De Backer JP, De Potter W, Vauquelin (1991) [3H]Rauwolscine behaves as an agonist for the 5-HT1A receptors in human frontal cortex membranes. Eur J Pharmacol 207:1–8
Eikmeier G, Berger M, Lodemann E, Muszynski K, Kaumeier S, Gastpar M (1991) Trimipramine — an atypical neuroleptic? Int Clin Psychopharmacol 6:147–153
Fleming WW, Westfall DP, De La Landi LS, Jellet LB (1972) Lognormal distribution of equieffective doses of norepinephrine and acetylcholine in several tissues. J Pharmacol Exp Ther 181:339–345
Fuller RW, Snoddy HD, Cohen ML (1984) Interactions of trazodone with serotonin neurons and receptors. Neuropharmacology 23:539–544
Gozlan H, El Mestikawy S, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptors using a new ligand: [3H]-PAT. Nature 305:140–142
Kanba S, Richelson E (1984) Histamine H1 receptors in human brain labeled with [3H]doxepin. Brain Res 304:1–7
Morrow AL, Creese I (1986) Characterization of alpha 1-adrenergic receptor subtypes in rat brain: a reevaluation of [3H]WB4104 and [3H]prazosin binding. Mol Pharmacol 29:321–330
Munson PJ, Rodbard D (1980) LIGAND: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239
Peroutka SJ (1986) Pharmacological differentiation and characterization of 5-HT1A, 5HT1B, and 5-HT1C binding sites in rat frontal cortex. J Neurochem 47[2]: 529–540
Reimherr FW, Chouinard G, Cohn CK, Cole JO, Itil T, M., LaPierre YD, Masco HL, Mendels J (1991) Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled multicenter comparison study in outpatients with major depression. J Clin Psychiatry 51:18–27
Richelson E (1993) Review of Antidepressants in the treatment of mood disorders. In: Dunner DL (ed) Current psychiatric therapy. Saunders, Philadelphia, pp 232–239
Richelson E, Nelson A (1984a) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230:94–102
Richelson E, Nelson A (1984b) Antagonism by neuroleptics of neurotransmitter receptors of normal human brain in vitro. Eur J Pharmacol 103:197–204
Smith WT, Glaudin V (1992) A placebo-controlled trial of paroxetine in the treatment of major depression. J Clin, Psychiatry 53:36–39
Stanton TT, Bolden-Watson C, Cusack B, Richelson E (1993) Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics. Biochem Pharmacol 45:2352–2354
Wander TJ, Nelson A, Okazaki H, Richelson E (1986) Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro. Eur J Pharmacol 132:115–121
Wander TJ, Nelson A, Okazaki H, Richelson E (1987) Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2A receptors of normal human brian in vitro. Eur J Pharmacol 143:279–282
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Cusack, B., Nelson, A. & Richelson, E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology 114, 559–565 (1994). https://doi.org/10.1007/BF02244985
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DOI: https://doi.org/10.1007/BF02244985