Pharmacological characterization and CNS effects of a novel highly selective α_2C‐adrenoceptor antagonist JP‐1302

Abstract

Background and purpose: Pharmacological validation of novel functions for the a 2A -, a 2B -, and a 2C -adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective a 2C -adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine). Experimental approach: Standard in vitro binding and antagonism assays were employed to demonstrate the a 2C -AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered a 2C -adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. Key results: JP-1302 displayed antagonism potencies (K B values) of 1,500, 2,200 and 16 nM at the human a 2A -, a 2B -, and a 2C -adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the a 2 -subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize a 2 -agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, a 2 -agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the a 2A -adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCPinduced prepulse-inhibition deficit. Conclusions and implications:The results provide further support for the hypothesis that specific antagonism of the a 2C -adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.

Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

“…vs JP: 102 ± 7.3%, n ¼ 5 and 6, respectively). The selected doses (2 mg/kg) approach saturation (Supplementary Figure 1) and are sufficient to produce robust behavioral effects in vivo (Sallinen et al, 2007). Thus, our findings indicate the a 2A subtype is the principle noradrenergic autoreceptor in the vBNST of both WKY and SD rats, and it exerts similar control over norepinephrine release in both strains.…”

JP‐1302: a new tool to shed light on the roles of α2C‐adrenoceptors in brain

“…Although this is not the first a 2C -selective compound to be identified, (OPC-28326 (4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-proprionylaminobenzoyl) piperidine) was noted by Sun et al (2001) as having a K i of 13.7, 3840 and 633 nM at a 2C , a 2A and a 2B -adrenoceptors, respectively), it is the first to have been examined behaviourally in rodents. Sallinen et al (2007) show that doses of JP-1302 in the range of 1-10 mmol kg À1 decrease immobility time in the FST to a level similar to that seen with 10-30 mmol kg À1 of the antidepressant desipramine: the data are thus consistent with the response of the a 2C knockout and overexpressing mice. In marked contrast, however, the compound did not disrupt PPI and even enhanced the measure somewhat after a dose of 30 mmol kg À1 .…”

“…In the paper by Sallinen et al (2007) in this issue, JP-1302 is described as a novel, highly selective a 2C -adrenoceptor antagonist with a K i at the human a 2C -receptor of 16 nM -about 100-fold higher affinity than for a 2A or a 2B . Although this is not the first a 2C -selective compound to be identified, (OPC-28326 (4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-proprionylaminobenzoyl) piperidine) was noted by Sun et al (2001) as having a K i of 13.7, 3840 and 633 nM at a 2C , a 2A and a 2B -adrenoceptors, respectively), it is the first to have been examined behaviourally in rodents.…”

Effect of Exercise on Serum Sex Hormones in Men

“…Some cross-sectional studies conducted in middle-aged and older men indicate that circulating testosterone concentrations may be higher in men who regularly exercise (3,40). Prospective, nonrandomized studies of resistance exercise over a few weeks either increased testosterone (50) or not (26,42), whereas one study of daily aerobic exercise together with a low-fat diet increased SHBG, which could counteract the biological activity of testosterone (60). To our knowledge, no randomized clinical trials have been published that have tested the chronic effects of aerobic exercise on a comprehensive panel of sex hormones in middle-aged to older men.…”