Adrenoceptor Antagonistic Properties of Some 1,4-Substituted Piperazine Derivatives
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ORIGINAL ARTICLES Department of Bioorganic Chemistry, Chair of Organic Chemistry1; Department of Pharmacodynamics2; Department of Cytobiology and Histochemistry, Laboratory of Pharmacobiology3, Faculty of Pharmacy Medical College; Faculty of Chemistry4, Jagiellonian University Krakow, Poland Synthesis, ␣-adrenoceptors affinity and ␣1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives H. Marona 1, M. Kubacka 2, B. Filipek 2, A. Siwek 3, M. Dybała 3, E. Szneler 4, T. Pociecha 1, A. Gunia 1, A. M. Waszkielewicz 1 Received March 24, 2011, accepted April 25, 2011 Dr. Anna M. Waszkielewicz, Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland [email protected] Pharmazie 66: 733–739 (2011) doi: 10.1691/ph.2011.1543 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-phenoxy- ethyl)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 ␣1- and ␣2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioli- gand, respectively. Furthermore ␣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. Antago- nistic potency stayed in agreement with radioligand binding results. The most active compounds (1–5) 3 displaced [ H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1−13.1 nM). Compound 10 showed slightly lower affinity for ␣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 gaveapA2 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 ␣1- affinity properties with a Ki(␣1) value of 2.1 nM and it was 61.05 fold more selective toward ␣1 than ␣2- receptors. The best properties showed 1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4)withaKi(␣1) value of 2.4 nM, a 142.13 fold better selectivity to ␣1-over␣2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising com- pounds possessed an 1-(o-methoxyphenyl)piperazine moiety which probably plays an important role in the affinity to ␣-adrenoceptors. 1. Introduction Considering the physiological function of ␣-adrenoceptors lig- ands both agonist and antagonists of those receptors were intro- The adrenergic receptors (AR) belong to the family of G-protein duced to the pharmacotherapy and are currently used as medica- coupled seven-transmembrane spanning receptors. They are tions. ␣1-Antagonists have been used with considerable success divided into three subclasses: ␣1, ␣2 and , and further into sev- in the treatment of hypertension over the past two decades. It eral subtypes (i.e. ␣1A, ␣1B, ␣1D, ␣2A, ␣2B, ␣2C, 1, 2, 3). The can be expected that their well established status will not change classification is based on structural similarity, localization and as overactivity of the symphatetic nervous system constitutes a pharmacology as well as on cloning techniques (Bishop 2007; common phenomenon in resistant forms of hypertension. Addi- ␣ Docherty 1998; Gauthier et al. 2007). The -adrenoceptors are tively ␣1-antagonists are currently first-line therapy for lower involved in central and peripheral nervous system functions urinary tract symptoms (LUTS) associated with benign prostatic (Gyires et al. 2009) while -adrenoceptors are mainly responsi- hyperplasia (BPH). They improve both symptom score and uri- ble for the physiological function of the cardiovascular system, nary flow in that condition. It is worth to mention that selective respiratory tract and of fat tissue (Johnson 2006). More detailed urinary ␣1-blockers (␣1A/␣1D) constitute important treatment ␣1 receptors roles are connected with vascular smooth muscle tools for hypertensive patients with BPH since such patients contraction, increasing blood pressure, dilation of the pupil, the are best treated by the separate management of each condition human prostate smooth muscle contraction (Jain et al. 2008) (Schwinn and Roehrborn 2008; Sica 2005). Substances with ␣2- as well as regulation of cerebral microcirculation (Yokoo et al. adrenoceptor agonist activity are used as hypotensive agents but 2000). On the other hand ␣2 receptors are responsible for lower- this role is currently not important. However new fields of their ing blood pressure, sedation, analgesia, anesthesia, inhibition of application have occurred, particularly in the management of intestinal secretion, aggregation of the platelets and inhibition pain and anesthesia (Crassous et al. 2007; Gyires et al. 2009). of neurotransmitters release (Jain et al. 2008; Giovannoni et al. In this context, the search for ␣-adrenoceptor antagonists con- 2009; Gyires et al. 2009). stitutes an important area in medicinal chemistry. Furthermore, Pharmazie 66 (2011) 733 ORIGINAL ARTICLES Scheme 1: Synthesis of compounds 1–8 new applications are under investigation, so the clinical utility of 197.9 ± 40.8, 252.3 ± 49.7, 282.1 ± 39.0 nM, respectively. At both antagonist and agonists may expand in the future (Crassous the same time all substances proved ␣1 antagonistic properties et al. 2007). by showing hypotensive activity in normotensive rats. The sub- In recent years various new adrenergic receptor ligands have stances showed also 1-receptors binding properties as well as been synthesized. A large group of them contains an arylpiper- antiarrhythmic activity (Maciag˛ et al. 2003). azine moiety and more detailed – a phenylpiperazine moiety Taking into consideration those facts and our former experience (Betti et al. 2004; Bremner et al. 2000; Ismail et al. 2006; we synthesized a series of 1,4-substituted piperazine deriva- Pittalá et al. 2006). The encouraging fact is that potent tives. Among them there were both aroxyethyl and aroxypropyl ␣-receptors antagonists – prazosin, terazosin and doxazosin, derivatives of piperazine, in addition compounds 9, 10 and which have a well established position in pharmacotherapy, 11 contained a structural moiety of propranolol while com- posses a structural fragment of piperazine (Heran et al. 2009). pounds 1–5 and 10 possessed a 1-(o-methoxyphenyl)piperazine It is also worth to mention other ␣-receptors blockers urapidil fragment in their molecule. All compounds were subjected and naftopidil are containing an 1-(o-methoxyphenyl)piperazine to preliminary pharmacological screening. The present paper moiety (Cherney and Straus 2002; Muramatsu et al. 1991). reports on the results of their in vitro affinity to ␣1 and Our previous research has dealt with the synthesis and biological ␣2-adrenoceptors as well as their antagonistic properties at ␣1- activity of compounds in the group of 1,4-substituted piper- adrenoceptors on isolated rat aorta. azine derivatives that proved ␣1- and ␣2-adrenoceptors binding properties (Maciag˛ et al. 2003, 2008; Marona et al. 2008). The best results showed aroxyethylpiperazine derivatives e.i. 2. Investigations and results 1-(4-methoxyphenoxyethyl)-, 1-(2,6-dimethylphenoxyethyl)- and 1-(4-methylphenoxyethy)-4-(2-methoxyphenyl)piperazine 2.1. Chemical synthesis dihydrochlorides with Ki values related to inhibiting in vitro Synthesis of compounds 1–8 is shown in Scheme 1. 3 [ H]prazosin binding to cortical ␣1-receptors of 26.0 ± 6.9, Compounds 1–5 were obtained in reaction between 1- 87.5 ± 19.0, 84.6 ± 16.1 nM and Ki values related to inhibit- (2-methoxyphenyl)piperazine and appropriate phenoxyalkyl 3 ing in vitro [ H]clonidine binding to cortical ␣2-receptor of bromides carried out in toluene in the presence of anhydrous 734 Pharmazie 66 (2011) ORIGINAL ARTICLES Scheme 2: Synthesis of compounds 9–11 potassium carbonate according to well known procedures slightly lower affinity for the ␣1-adrenoceptor (Ki = 781 nM), (Maciag˛ et al. 2003; Marona et al. 2004). Compounds 6–8 whereas other compounds (6–9, 11, 12) had a low affinity for were synthesized in multistep reaction according to earlier both ␣1- and ␣2-adrenoceptors, moderately inhibiting radioli- published methodology (Marona et al. 2004, 2009). At first gands binding in the M-range. The most selective compounds appropriate phenoxyethyl bromides were used in the reaction (4 and 5) showed a 142.1- and 61-fold higher affinity for ␣1- with 1-ethoxycarbonylpiperazine in n-butanol in the presence of than for ␣2-adrenoceptors. potassium carbonate, intermediate products were not separated. Hydrolysis in 85% potassium hydroxide of derivatives gave the 2.2.2. Functional bioassays results corresponding 1-[2-(phenoxyethyl)piperazine]. The raw prod- ucts were used in further reaction with another appropriate The antagonist activity of compounds 1–5 and 10 toward ␣ phenoxyethyl bromides. Bases received as oils were converted 1-adrenoceptors present in rat aorta from adult Wistar rats into hydrochlorides using an excess of ethanol saturated with was assessed by inhibition of phenylephrine induced contrac- gas hydrochloride. Raw salts were recrystallized from ethanol.