The Versatile 2‐Substituted Imidazoline Nucleus as a Structural Motif of Ligands Directed to the Serotonin 5‐HT_1A Receptor

Abstract

The involvement of the serotonin 5‐HT1A receptor (5‐HT1A‐R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2‐substituted imidazoline nucleus as a structural motif interact with 5‐HT1A‐R. Therefore, we examined the 5‐HT1A‐R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2‐position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5‐HT1A‐R and to identify the structural features favoring 5‐HT1A‐R interaction. Structure–activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5‐HT1A‐R recognition and activation. We also highlighted the potent antidepressant‐like effect (mouse forced swimming test) of (S)‐(+)‐19 [(S)‐(+)‐naphtyline] at very low dose (0.01 mg kg−1). This effect was clearly mediated by 5‐HT1A, as it was significantly reduced by pretreatment with the 5‐HT1A antagonist WAY100635.

The Use of the Selective Imidazoline I1 Receptor Agonist Carbophenyline as a Strategy for Neuropathic Pain Relief: Preclinical Evaluation in a Mouse Model of Oxaliplatin-Induced Neurotoxicity

“…Some of these imidazoline ligands demonstrated to be efficacious as anti-neuropathic agents. In particular, in addition to the already mentioned I 2 ligand phenyzoline (1), characterized by a -CH 2 CH 2 -bridge, the dual α 2 /5-HT 1A receptor agonist S-(-)-biphenyline (4) [47,48], bearing an -OCH(CH 3 )-bridge and an ortho phenyl substituent in the aromatic ring, showed a significant painrelieving effect in a rat model of neuropathic pain [49]. The isosteric substitution of the oxygen atom of the bridge with a CH 2 group produced derivative carbophenyline, characterized by an interesting modulation of the biological profile.…”

Spinal α2‐adrenoceptors and neuropathic pain modulation; therapeutic target

“…It has been demonstrated that the ( S )‐(−) enantiomer of biphenyline, described as an α 2 adrenoceptor (Gentili et al, ) and 5‐HT 1A receptor (Del Bello et al, ) agonist, behaved as a potent and long‐lasting antinociceptive agent in algesiometric paradigms (Gentili et al, ). Considering the important role played by both 5‐HT 1A receptors and α 2 adrenoceptors in nociception, Di Cesare Mannelli et al () are presented with a novel pharmacodynamic approach for the treatment of neuropathic pain.…”

“…It has been demonstrated that the (S)-(−) enantiomer of biphenyline, described as an α 2 adrenoceptor (Gentili et al, 2004) and 5-HT 1A receptor (Del Bello et al, 2016) agonist, behaved as a potent and long-lasting antinociceptive agent in algesiometric paradigms (Gentili et al, 2004). induced an analgesic effect similar to (S)-(−)-1 administered at a 100fold lower dose.…”

4WD to Travel Inside the 5-HT1A Receptor World

“…In particular, (S)-naphthaline (139) shows the highest 5-HT 1A R affinity within the series (Figure 41). In mice it displays antidepressantlike effect at a very low dose (0.01 mg/Kg) and proves to be more efficacious and potent than amitriptyline (15 mg/kg), a tricyclic antidepressant commonly used in human therapy [52].…”