The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats

Abstract

We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.

Translocator protein mediates the anxiolytic and antidepressant effects of midazolam

“…The anxiolytic effect is indicated by an increase in the number of shocks that the rats receive following inhibition of the conflict between the desire to drink water and aversion to an electric shock (Kasahara et al, 2015;Qiu et al, 2015). The test was performed as described previously (Zhang et al, 2014a).…”

Anxiolytic‐like effects of the new arylpiperazine derivatives containing isonicotinic and picolinic nuclei: behavioral and biochemical studies

“…EPM stands out from these models by the fact that it uses natural stimuli such as fear of the new open spaces, which may also be anxiogenic for humans . Of note, several drugs, for example, BUS and DZ, exhibit characteristic anxiolytic effects in this test, upholding its high usefulness .…”

“…Among these are BUS, gepirone, ipsapirone, and tandospirone. These induce anxiolytic effects by stimulating both pre-and postsynaptic 5-HT 1A receptors [62][63][64][65]; at the same time, these compounds also interact with other neurotransmitter systems, such as dopaminergic and adrenergic [66][67][68].…”

Recent Advances in the Cycloaddition Reactions of 2‐Benzylidene‐1‐benzofuran‐3‐ones, and Their Sulfur, Nitrogen and Methylene Analogues

“…Sulfur ylide is a zwitterionic compound that can be divided into stable, semi-stable, and active sulfur ylides. [31] In 2018, Huang's group formed an indole [5,3] spirocycles 40 by [2 + 1] cycloaddition reactions between (Z)-2-ylideneoxindoles 27 and sulfur ylides 39, which had an excellent yield and dr value (Scheme 7a). [32] In 2019, this group also used α, β-unsaturated imines 41 or 42 and the sulfur ylide-containing trifluoromethyl group 43 to obtain spiro compounds 44 with an excellent yield and dr value (Scheme 7b).…”

“…The core structures of benzothiophene, benzofuran, indole and indene are found in many natural products and pharmaceuticals, which are studied in materials science. [1] Examples include Raloxifene, [2] AP521, [3] MJ-III-65, [4] and Strobilanthoside [5] (Figure 1). The construction of benzothiophene, benzofuran, indole, and indene derivatives is a significant challenge in organic synthesis.…”