Synthesis, alpha-adrenoceptors affinity and alpha(1)-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives

Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy Medical College, Jagiellonian University Krakow, Poland.
Pharmazie (Impact Factor: 1). 10/2011; 66(10):733-9. DOI: 10.1691/ph.2011.1543
Source: PubMed

ABSTRACT A series of different 1,4-substituted piperazine derivatives (1-11) was synthesized. It comprised 1-(substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (1-5); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (6-8) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (9-11). All compounds were evaluated for affinity toward alpha 1- and alpha 2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioligand, respectively. Furthermore alpha 1-antagonistic properties were checked for most promising compounds (1-5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antagonistic potency stayed in agreement with radioligand binding results. The most active compounds (1-5) displaced [3H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1-13.1 nM). Compound 10 showed slightly lower affinity for alpha 1-adrenoceptor (Ki = 781 nM). Compounds 2-5 displayed the strongest antagonistic activity with pA2 values ranging from 8.441 to 8.807. Compound 1 gave a pA2 value of 7.868, while compound 10 showed the weakest antagonistic potency, giving a pA2 value of 6.374. 1-[3-(2-Chloro-6-methylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (5) showed the best alpha 1- affinity properties with a Ki(alpha 1) value of 2.1 nM and it was 61.05 fold more selective toward alpha 1 than alpha 2-receptors. The best properties showed 1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4) with a Ki(alpha 1) value of 2.4 nM, a 142.13 fold better selectivity to alpha 1 - over alpha 2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising compounds possessed an 1-(o-methoxyphenyl)piperazine moiety which probably plays an important role in the affinity to alpha-adrenoceptors.


Available from: Anna M Waszkielewicz, Dec 02, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: α 1-AR antagonists are currently first-line therapy for lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). In this study, we report the synthesis of a new series of arylpiperazine derivatives containing acetophenone (3-17) which possess α 1-adrenoreceptor blocking activity. The in vitro α 1-adrenoreceptor blocking activity of each derivative was first screened using rabbit thoracic aortic rings by measuring the relaxation response (%) activated by (–)-noradrenaline (3 μM). Compounds 6 and 7 with 2,5-dimethoxy and 2-ethoxy substituent were found to have significant vasodilatory effect. Since the presence of a chiral carbon in the structure, 6 and 7 together with their enantiomers 14-17 were further evaluated by testing diastolic effect on rabbit thoracic aorta, prostate and bladder smooth muscle. The S-enantiomer was found to have more potent diastolic activity than the R-enantiomer and racemate, 17 being the most effective α 1-adrenoreceptor antagonist. In order to assess tissue selectivity, the antagonistic effect of 17 on the (-)-noradrenaline induced contractile response of isolated rat vas deferens (α1A), spleen (α1B) and aorta (α1D) was characterized finally. Compared with naftopidil (1) and terazosin, compound 17 exhibited higher selectivity (18-fold) for the α1D-adrenoceptor subtype as compared to the α1B-adrenoceptor subtype, indicating less cardiovascular side effects for the treatment of LUTS/BPH. These data suggest that the acetophenone is a new effective adrenergic receptor ligand as well as incentivizes further research regarding pharmacological properties of chiral molecules.
    Pharmazie 08/2014; 69(8). DOI:10.1691/ph.2014.3971 · 1.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of new derivatives of N-(2-methoxyphenyl)piperazine have been synthesized for their affinity towards serotonergic receptors and for their potential antidepressant-like activity. They have been evaluated towards receptors 5-HT1A, 5-HT6, and 5-HT7, as well as in vivo in the tail suspension, locomotor activity, and motor coordination tests. All the tested compounds proved very good affinities towards 5-HT1A and 5-HT7 receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity towards receptors Ki<1 nM (5-HT1A), and Ki=34 nM (5-HT7). Antidepressant-like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.) and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity ED50 (locomotor test, mice, i.p.)=17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) =53.2 mg/kg b.w.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 07/2014; 85(3). DOI:10.1111/cbdd.12394 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The main goal of this study was to assess antiarrhythmic and hypotensive activity of new 2-methoxyphenylpiperazine derivatives of xanthone. In order to better understand mechanism of action of studied compounds, their ability to antagonise the increase in blood pressure elicited by adrenaline, noradrenaline and methoxamine, as well as the antagonistic properties for α1-adrenoceptors on isolated rat aorta were evaluated. Therapeutic antiarrhythmic activity was investigated in adrenaline-induced model of arrhythmia. Hypotensive activity in normotensive rats was evaluated after oral administration. Influence on blood vasopressor response and α1-adrenoceptors in rat thoracic aorta was evaluated to determine if the observed cardiovascular effects could be related to α1-adrenolytic properties. Tested compounds produced antiarrhythmic and hypotensive activity. The most active compound was MH-99 - (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride. All studied compounds showed α1-adrenolytic properties in the in vivo and in vitro tests. The results indicate that new valuable compounds with antiarrhythmic and hypotensive activity might be found in the group of xanthone derivatives. Further pharmacological utility of these compounds should be investigated.
    European journal of pharmacology 04/2014; 735. DOI:10.1016/j.ejphar.2014.04.010 · 2.68 Impact Factor