Potential Antidepressants Displayed Combined α₂-Adrenoceptor Antagonist and Monoamine Uptake Inhibitor Properties

Abstract

Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-naphthalenyl)methyl]-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

“…It should not be excluded that their efficacy in the such disorders may also depend on the involvement of 5-HT 1A receptor, at which ligands, such as yohimbine and idazoxan, show good affinity [101]. From this point of view, the association of the α 2 -antagonist and the 5-HT reuptake inhibitor (SSRI) activities is strategic, as it occurs, for example, in the case of mianserine (27) and mirtazapine (28) [102], napamezole (29) [103], Abbott's A-80426 (30) [104], whose (R) enantiomer is the most potent isomer, or Servier's S-34324 (31) [105]. α 2 -Antagonism, due to the blockade of adrenergic autoreceptors, offers the advantages of accelerating the onset of action and of improving sexual function, whose reduction is one of the side effects of 5-HT uptake inhibition [95].…”

“…From this point of view, an interesting candidate is 4(5)-[(5-fluoroindan-2-yl)methyl]4,5-dihydroimidazole (31), belonging to a series of molecules structurally related to the above mentioned α 2 -antagonist atipamezole (14). In fact, the fluorine atom at position 5 slightly increases affinity at SER uptake sites while it slightly depresses affinity at α 2 -ARs and significantly at NA uptake sites, conferring an equilibrated α 2 -AR antagonist and SER uptake inhibitor profile on the molecule ( Table 6) [105]. In the same study, the analysis of a series of compounds structurally related to napamezole (29) reveals that α 2 -ARs affinity is favored by the presence of an sp 2 nitrogen atom in an extended conformation four-atom chain linked to an aromatic ring.…”

Indanes—Properties, Preparation, and Presence in Ligands for G Protein Coupled Receptors

“…Another structurally similar α 2 adrenoceptor antagonist was designed to combine the properties of 22 with the monoamine uptake inhibition properties of napamezole 24 , thereby creating antidepressant effects. Compound 25 had the best balance between affinity for α 2 adrenoceptors and serotonin‐norepinephrine reuptake inhibitor properties . The change from indane to indene affected only the α 2 adrenoceptors while a further change to benzofuran solely affected the serotonin reuptake inhibition.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…99 Based on such considerations, several groups have designed centrally active agents that both antagonize ␣ 2 -ARs and suppress reuptake of 5-HT or NA (or both) in vivo. 124,125 For example, the spiroimidazoline ␣ 2 -AR antagonist/SNRI, S35966 (FIG. 6), elicits marked increases in frontocortical levels of NA, DA, and 5-HT, compared with SNRIs, is more potent in behavioral models of antidepressant activity, and it more rapidly downregulates 5-HT 2A receptors in frontal cortex, a cellular marker of therapeutic activity.…”