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

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 (p K i = 5.6) in contrast to mianserin (p K i = 7.4). Both (±)Org 3770 and mianserin facilitated the release of [ 3H]NA in slices of cortex. The effects of NA mediated by α 2-adrenoceptors on the release of both [ 3H]NA or [ 3H]serotonin ([ 3H]5-HT) were antagonized by (+)Org 3770 with p K i values of 8.4 and 8.1, respectively. However, (−)Org 3770 only antagonized the effect of NA on the release of [ 3H]5-HT (pA 2 = 7.7). The binding of [ 2H]rauwolscine to α 2-adrenoceptors was inhibited by (±)Org 3770 and mianserin with identical affinity (p K i = 7.0), whereas the binding of [ 3H]prazosine to α 1-adrenoceptors was less potently affected by (±)Org 3770 (p K i = 6.4) than by mianserin (p K i = 7.1). A similar difference was found for α 1- and α 2-adrenoceptors in vas deferens of the rat. The binding of [ 3H]mianserin to 5-HT 2 receptors was less potently blocked by (±)Org 3770 (p K i = 8.1) than by mianserin (p K i = 9.4) while the binding of [ 3H]mepyramine to histamine-1 receptors was more potently affected by (±)Org 3770 (p K i = 9.3) than by mianserin (p K i = 8.75). The binding of [ 3H]quinuclidinylbenzilate to muscarinic cholinergic receptors was blocked equally by (±)Org 3770 (p K i = 6.1) and mianserin (p k i = 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 α 2-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.