Elsevier

Neuropharmacology

Volume 27, Issue 4, April 1988, Pages 399-408
Neuropharmacology

Neurochemical and autonomic pharmacological profiles of the 6-aza-analogue of mianserin, org 3770 and its enantiomers

https://doi.org/10.1016/0028-3908(88)90149-9Get rights and content

Abstract

The neurochemical and autonomic pharmacological profile of l,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a]pyrido[2,3-c][2] benzazepine (±)Org 3770) and the related antidepressant drug, mianserin, have been compared. The uptake of [3H] noradrenaline ([3H]NA) in vitro was weakly affected by (±)Org 3770 (pKi = 5.6) in contrast to mianserin (pKi = 7.4). Both (±)Org 3770 and mianserin facilitated the release of [3H]NA in slices of cortex. The effects of NA mediated by α2-adrenoceptors on the release of both [3H]NA or [3H]serotonin ([3H]5-HT) were antagonized by (+)Org 3770 with pKi values of 8.4 and 8.1, respectively. However, (−)Org 3770 only antagonized the effect of NA on the release of [3H]5-HT (pA2 = 7.7). The binding of [2H]rauwolscine to α2-adrenoceptors was inhibited by (±)Org 3770 and mianserin with identical affinity (pKi = 7.0), whereas the binding of [3H]prazosine to α1-adrenoceptors was less potently affected by (±)Org 3770 (pKi = 6.4) than by mianserin (pKi = 7.1). A similar difference was found for α1- and α2-adrenoceptors in vas deferens of the rat. The binding of [3H]mianserin to 5-HT2 receptors was less potently blocked by (±)Org 3770 (pKi = 8.1) than by mianserin (pKi = 9.4) while the binding of [3H]mepyramine to histamine-1 receptors was more potently affected by (±)Org 3770 (pKi = 9.3) than by mianserin (pKi = 8.75). The binding of [3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (±)Org 3770 (pKi = 6.1) and mianserin (pki = 6.3). Similar data on tryptamine-d, histamine-1 and muscarinic cholinergic receptors in isolated organs were obtained. A prominent role for the blockade of α2-adrenoceptors in the therapeutic effects of mianserin and (±)Org 3770 in depression is suggested, probably excluding a role of inhibition of the uptake of NA.

References (44)

  • B.D. Perry et al.

    [3H]Rauwolscine (α-Yohimbine): a specific antagonist radioligand for brain α2-adrenergic receptors

    Eur. J. Pharmac.

    (1981)
  • M. Raiteri et al.

    A simple apparatus for studying the release of neurotransmitters from synaptosomes

    Eur. J. Pharmac.

    (1974)
  • J.E. Smith et al.

    A method for concurrent measurement of picomole quantities of acetylcholine, choline, dopamine, norepinephrine, serotonin, 5-hydroxytrypto-phan, 5-hydroxyindoleacetic acid, tryptophan, tyrosine, glycine, aspartate, glutamate, alanine and gamma-aminobutyric acid in single tissue samples from different areas of rat central nervous system

    Analyt. Biochem.

    (1975)
  • M. Sugrue

    Chronic antidepressant therapy and associated changes in central monoaminergie receptor functioning

    Pharmac. Ther.

    (1983)
  • M.L. Vargas et al.

    Mechanism of action of B-HT 933 (azepexole) in rat vas deferons and guinea pig ileum

    Eur. J. Pharmac.

    (1985)
  • P.A. Baumann et al.

    Blockade of pre-synaptic α-receptors and of amine uptake in the rat brain by the antidepressant mianserin

    Naunyn-Schmiedebergs Arch. Pharmac.

    (1977)
  • P. Blier et al.

    Effects of the two antidepressant drugs mainserin and indalpine on the serotonergic system: single cell studies in the rat

    Psychopharmacology

    (1984)
  • J.L. Claghorn et al.

    The effectiveness of 6-azamianserin (Org 3770) in depressed outpatients

    Psychopharmac. Bull.

    (1987)
  • J.C. Doxey et al.

    In vitro and in vivo studies on RX 781094: a selective, potent and specific antagonist of α2-adrenoceptors

    Br. J. Pharmac.

    (1983)
  • G.M. Drew et al.

    α2-Adrenoceptors mediate clonidine-induced sedation in the rat

    Br. J. Pharmac.

    (1979)
  • R.S. Duman et al.

    Effect of imipramine and adrenocorticotrophin administration on the rat brain norepinephrine-coupled cyclic nucleotide generating system: alterations in alpha and beta adrenergic components

    J. Pharmac. exp. Ther.

    (1985)
  • M. Fink et al.

    Pharmaco-EEG study of 6-aza mianserin (Org 3770): dissociation of EEG and pharmacological predictions of antidepressant activity

    Psychopharmacology

    (1982)
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