Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative.

The novel bicyclic compound Wy-45,030 [1-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl cyclohexanol, hydrochloride] exhibited a neurochemical profile predictive of antidepressant activity. Like the tricyclic antidepressants, it inhibited rat brain imipramine receptor binding and synaptosomal monoamine uptake (dopamine as well as norepinephrine and serotonin). It did not inhibit monoamine oxidase.

Antidepressants and protein kinases: desipramine treatment affects pineal gland cAMP-dependent protein kinase activity.

To further describe the molecular mechanisms involved in reductions in noradrenergic responsiveness induced by antidepressants, the effects of antidepressant treatment on the rat pineal gland cAMP-dependent protein kinase system were examined. The concentration of cyclic AMP-dependent protein kinase activity was reduced 24 h after acute treatment with desipramine, as well as in animals treated repeatedly with desipramine. Assays performed in the presence of cAMP protein kinase inhibitor showed no significant effects of either acute or repeated desipramine treatment on the concentration of cAMP-independent protein kinase activity.

Antidepressants and protein kinases: inhibition of Ca2+-regulated myosin phosphorylation by fluoxetine and iprindole.

The effects of several antidepressant and antipsychotic agents on Ca2+-calmodulin-regulated myosin light chain phosphorylation were evaluated. At a concentration of 100 microM, the antidepressant agents buproprion, mianserin and maprotiline were ineffective; zimelidine, desipramine and imipramine produced 40-50% inhibition; and iprindole and fluoxetine produced 75-90% inhibition. The efficacies of iprindole and fluoxetine were similar to the phenothiazine antipsychotics chlorpromazine and trifluoperazine.

DMI, Wy-45,030, Wy-45,881 and ciramadol inhibit locus coeruleus neuronal activity.

Wy-45,030 and Wy-45,881 block the uptake of norepinephrine and serotonin in rat brain synaptosomal preparations and share several in vivo and in vitro effects with known tricyclic antidepressants. To further characterize their activity, these compounds were compared to desipramine and ciramadol in electrophysiological studies of their acute effects on noradrenergic neuronal activity. All four compounds inhibited locus coeruleus neuronal activity with a rank order of potency of desipramine greater than Wy-45,881 greater than Wy-45,030 greater than ciramadol.

Suppression of histamine-induced adrenocorticotropic hormone release by antihistamines and antidepressants.

The antihistaminic activity of many antidepressant drugs is well documented in vitro but has not been investigated as thoroughly in vivo. In the course of an investigation of the roles of H1 and H2 receptors in histamine-induced adrenocorticotropic hormone (ACTH) release in rats, it was observed that several antidepressants were potent inhibitors of this response. Male Sprague-Dawley rats were injected with test drugs and then with histamine or histamine agonists.