Copyright © 2001 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2001, 53, 395–401 ISSN 1230-6002

SHORT COMMUNICATION

ARYLPIPERAZINE DERIVATIVES OF 3-PROPYL-b-TETRALONOHYDANTOIN AS NEW 5-HT1A AND 5-HT2A RECEPTOR LIGANDS

Hanna Byrtus1, Maciej Paw³owski1, Beata Duszyñska2, Anna Weso³owska3, Ewa Chojnacka-Wójcik3, Andrzej J. Bojarski2,# Department of Pharmaceutical Chemistry, Collegium Medicum, Jagiellonian University, Medyczna 9, PL 30-688 Kraków, Poland; Department of Medicinal Chemistry, !Department of New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Arylpiperazine derivatives of 3-propyl-b-tetralonohydantoin as new 5-HT ) and 5-HT ) receptor ligands. H. BYRTUS, M. PAW£OWSKI, B. DUSZYÑSKA, A. WESO£OWSKA, E. CHOJNACKA-WÓJCIK, A.J. BOJARSKI. Pol. J. Pharmacol., 2001, 53, 395–401.

A series of new analogues of 3-[3-(4-arylpiperazinyl)-propyl]-cyclo- hexane-1’,5-spirohydantoin (2), with aromatic ring fused in amide moiety (4–9) were synthesized and evaluated for affinity at 5-HT ) and 5-HT ) re- ceptors. The influence of the substitution mode in the phenyl ring of phenyl- piperazine moiety on the affinity for both receptors has been discussed. The most potent 5-HT ) (9, KE = 53 nM) and 5-HT ) (4, 6, 8 and 9; KE = 14–76 nM) ligands were evaluated in in vivo tests. The obtained results indicate that all in vivo tested compounds showed pharmacological profile of 5-HT ) an- tagonists. Additionally, a m-CF! derivative (9), behaved like a partial agonist (agonist of pre- and antagonist of postsynaptic) of 5-HT ) receptors and may offer a new lead for the development of potential psychotropic agents.

Key words: 1-arylpiperazine derivatives, 3-propyl-b-tetralonohydantoins, 5-HT ) and 5-HT ) receptor affinity, structure-activity relationship

 correspondence; e-mail: [email protected] H. Byrtus, M. Paw³owski, B. Duszyñska, A. Weso³owska, E. Chojnacka-Wójcik, A.J. Bojarski

INTRODUCTION derivatives of 1,3-dioxoperhydroimidazo[1,5-a]py- ridine) as new selective 5-HT1A receptor ligands. Actions of a large number of psychopharma- Compound 3 [15], a direct analogue of the above- ceuticals (e.g. anxiolytics, antidepressants and aty- mentioned structures 1 and 2, was several times pical antipsychotics) are mediated, at least in part, more active at 5-HT1A receptors (Ki = 154 nM vs. via interactions with various serotonin (5-HT) re- 1000 and 830 nM, respectively). These results ceptors. Recently, a considerable attention has cen- prompted us to continue our search for mixed tered on compounds acting at both 5-HT1A and 5-HT1A/5-HT2A receptor ligands within arylpipera- 5-HT2A receptors as one of the possible strategies zine derivatives of spirohydantoin. A series of new for development of new psychotropic agents [19]. analogues with aromatic ring fused in amide moi- 5,5-Disubstituted hydantoins and their N3-mo- ety was synthesized (Tab. 1) and the influence of dified derivatives showed a wide spectrum of acti- structural changes on the 5-HT1A/5-HT2A affinity vity on the central nervous system mediated by and pharmacological profile of newly synthesized 5-HT1A, 5-HT2A, a1-adrenergic, dopaminergic D2, compounds has been discussed. and other receptors [4, 12, 13, 15, 20]. In previous studies we have demonstrated that in 3-(w-aminoalkyl)-5,5-dialkyl (or 1’,5-spirocyclo- MATERIALS and METHODS alkyl) hydantoins containing 1-phenylpiperazine or 1-(o-methoxyphenyl)-piperazine fragment in 3-po- CHEMISTRY sition, the terminal hydantoin moiety plays an im- b portant role in the stabilization of the 5-HT1A and The -tetralonohydantoin (7,8-benzo-1,3-diaza- 5-HT2A receptor-ligand complexes [4, 20]. Two spiro-[4,5]-decane-2,4-dione) (II) used in this stu- compounds: 1’,5-cyclopentanespiro-[3-(4-phenyl-1- dy was prepared from the ketone (I) by Bucherer -piperazinyl)-propyl]-hydantoin (1) and its 1’,5-cy- Berg reaction with modifications described by clohexanespiro analogue (2, Fig. 1) were found to Goodson et al. [9]. Compounds 4–9 were obtained exhibit high 5-HT receptor affinity (K =34and in several-step procedure involving alkylation of 2A i b 37 nM, respectively), but unfortunately they had -tetralonohydantoin (II) with 1-bromo-3-chloro- low affinity for 5-HT receptors. At the same time propane in acetone medium in the presence of 1A g Lopez-Rodriguez et al. [15] reported a series of K2CO3. Condensation of 3- -chloropropylo inter- structurally related compounds (phenylpiperazine mediate (III) with appropriate phenylpiperazine derivative in anhydrous ethanol gave the final O bases 4–9 (Fig. 2). The purity of the final products was confirmed N N by thin layer chromatography using Kieselgel 60 N N F254 plates (Merck) and respective solvent systems: O H acetone : isopropanol : chloroform (20 : 10 : 1) for 4, 1 5 and 9 or methanol : 25% NH3 (100 : 1.5) for 6–8. The structure of compounds (free bases) was con- O firmed by 1H-NMR and UV spectra (data not N N shown). For biochemical studies free bases were converted into hydrochloride salts and their mo- N N O H lecular formulas were established on the basis of 2 their elemental analyses (C, H, N). The properties of the products are given in Table 1. O

N N PHARMACOLOGY N N In vitro O studies – binding experiments

3 Radioligand binding experiments were conduc- ted on the rat hippocampus for 5-HT1A receptors, Fig. 1. Structure of the selected hydantoin derivatives and on the cortex for 5-HT2A receptors according

396 Pol. J. Pharmacol., 2001, 53, 395–401 5-HT ) AND 5-HT ) RECEPTOR LIGANDS

O O a b O HN NH HN N Cl I II III O O

c

O R d HN N N N 4–9 ×HCl

O 4–9

Fig. 2. Method for preparation of compounds 4–9. (a) KCN, (NH") CO!, 50% EtOH, reflux 14 h; (b) Br(CH )!Cl, K CO!, (CH!) CO, reflux 8 h; (c) 1-phenylpiperazine derivative, anhydr. EtOH, reflux 20 h; (d) 36% HCl

Table 1. Structures, physicochemical properties and 5-HT ) and 5-HT ) binding data of compounds 4–9 O

N N R N N O H

M.p. [°C] KE ± SEM [nM] Yield [%] (base) Molecular formula* Compound R Cryst. solvent Molecular weight (salt) Base salt 5-HT ) 5-HT )

4 H 170–172 248–250 50.0 C #H!N"O · HCl 70±1 34±2 ethanol 454.98

5 o-OCH! 188–189 246–247 49.0 C $H! N"O! · HCl 92±12 462±10 ethanol/acetone 485.01

6 m-Cl 148–150 247–248 53.3 C #H 'N"O Cl · HCl 96±1 17±2 ethanol/acetone 489.43

7 o-F 161–163 263–265 54.0 C #H 'N"O F · HCl 408 ± 2 117 ± 5 ethanol 472.97

8 p-F 157–160 268–270 50.5 C #H 'N"O F · HCl 950 ± 21 14 ± 2 ethanol 472.97

9 m-CF! 160–163 272–275 56.0 C $H 'N"O F! · HCl 53±1 76±4 ethanol 502.97

* The values established by elemental analysis were within 0.4% in relation to the calculated values

ISSN 1230-6002 397 H. Byrtus, M. Paw³owski, B. Duszyñska, A. Weso³owska, E. Chojnacka-Wójcik, A.J. Bojarski to the published procedures [3]. The used radio- pound or 8-OH-DPAT administration) as follows: ligands were [3H]-8-OH-DPAT (190 Ci/mmol, Am- 0 – lower incisors not visible, 0.5 – partly visible, ersham) and [3H]-ketanserin (60 Ci/mmol, NEN 1 – completely visible. The maximum score, sum- Chemicals) for 5-HT1A and 5-HT2A receptors, re- med, amounted to 3 for each rat. The effect of the spectively. KE values were determined on the basis investigated compound on the LLR induced by of at least three competition binding experiments in 8-OH-DPAT (1 mg/kg) was tested in a separate ex- which the tested compounds were used at concen- periment. The investigated compound was admi- trations of 10–10–10–3 M, run in triplicate. nistered 45 min before 8-OH-DPAT, and the animals were scored at 15, 30 and 45 min after 8-OH-DPAT In vivo studies administration. The experiments were carried out on male Al- Body temperature in mice. The effects of bino–Swiss mice (25–30 g) and male Wistar rats compound 9 or 8-OH-DPAT (5 mg/kg), given alone, (260–300 g). The animals were kept at an ambient on the rectal body temperature in mice (measured temperature of 20 ± 1°C throughout the experiment with an Ellab thermometer) were recorded 30, 60, and had free access to food (standard laboratory 90, and 120 min after its administration. In a sepa- pellets, LSM) and tap water. All experiments were rate experiment, the effect of WAY 100635 on hy- conducted in the light phase on a natural light-dark pothermia induced by the investigated compound cycle (from July to December), between 9 a.m. and or 8-OH-DPAT was tested. WAY 100635 (0.1 mg/kg) 2 p.m. 8-Hydroxy-2-(di-n-propylamino)tetralin hy- was administered 15 min before the tested com- drobromide (8-OH-DPAT, Research Biochemicals, pound and the rectal body temperature was re- Inc.), N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]- corded 30 and 60 min after the injection of the in- ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide tri- vestigated compound. hydrochloride (WAY 100635; synthesized by Dr. J. The results are expressed as a change in the Boksa, Institute of Pharmacology, Polish Academy body temperature (Dt) with respect to the basal of Sciences, Kraków, Poland) and (±)-1-(2,5-dime- body temperature, as measured at the beginning of thoxy-4-iodophenyl)-2-aminopropane hydrochlori- the experiments. de [(±)-DOI], Research Biochemicals, Inc.) were dissolved in saline. The investigated compounds were used in the form of freshly prepared suspen- RESULTS and DISCUSSION sions in 1% Tween 80. 8-OH-DPAT and WAY 100635 were injected subcutaneously (sc), (±)-DOI The investigated compounds exhibit moderate and the tested compounds were administered in- to low in vitro activity for 5-HT1A receptors, which traperitoneally (ip) in a volume of 10 ml/kg (mice) range from 53 nM for 9 to 950 nM for 8 (Tab. 1). or 2 ml/kg (rats). Each group consisted of 6–9 ani- Compounds 5, 6 and 9 show 5-HT1A affinity of the mals. The obtained data were analyzed by the New- same order as an unsubstituted 1-phenylpiperazine man-Keuls test. (PhP) derivative 4 (Ki = 70 nM). Introduction of the Head-twitch response in mice. In order to ha- fluorine atom into aromatic ring of PhP signifi- bituate mice to the experimental environment, each cantly decreased the observed 5-HT1A affinity to Ki animal was randomly transferred to a 12 cm (dia- values of 407 and 950 nM for o-F (7) and p-F (8) meter) × 20 cm (height) glass cage, lined with saw- derivatives, respectively. dust, 20 min before the treatment. Head twitches of All tested compounds demonstrate relatively mice were induced by (±)-DOI (2.5 mg/kg). Imme- high in vitro affinities for 5-HT2A receptors (Ki = diately after the treatment, the number of head 14–117 nM) except the o-OCH3 derivative 5 (Ki = twitches was counted during 20 min [6]. The inves- 462 nM; Tab.1). The most potent 5-HT2A ligands, tigated compounds were administered 60 min be- m-Cl-PhP (6, Ki =17nM)andp-F-PhP (8, Ki =14 fore (±)-DOI. nM) derivatives, were two times more active than Lower lip retraction (LLR) in rats. The LLR the starting compound 4 (Ki =34nM). was assessed according to the method described by Introduction of the phenyl ring in the terminal Berendsen et al. [1, 2]. The rats were individually part of spirohydantoin 2 [4] significantly increased placed in cages (30 × 25 × 25 cm) and were scored the 5-HT1A receptor affinity of 4 (Ki = 830 nM vs. three times (at 15, 30 and 45 min after tested com- 70 nM) whereas activity for 5-HT2A ones remained

398 Pol. J. Pharmacol., 2001, 53, 395–401 5-HT ) AND 5-HT ) RECEPTOR LIGANDS unchanged (Ki =37nMvs. 34 nM). Thus, this sim- as the reference ketanserin inhibited effectively the ple modification brought us near the desired in vi- (±)-DOI-induced head twitches in mice; ED50 va- tro profile of mixed 5-HT1A/5-HT2A ligand. In order lues of these compounds were between 3.1–9.1 to further increase the observed 5-HT1A affinity of mg/kg (Tab. 2), hence they may be classified as 4, we modified its structure by application of dif- 5-HT2A receptor antagonists. ferent arylpiperazine fragments. The influence of the substitution mode in the phenyl ring of aryl- Table 2. The effects of the investigated compounds on the (±)-DOI-induced head twitch response in mice piperazine moiety on 5-HT1A receptor affinity have already been thoroughly studied either in unsubsti- = Compound ED# (mg/kg, ip) tuted [8, 11, 16, 17], N-alkyl substituted [18] or complex arylpiperazine derivatives [5, 13, 15]. On 4 6.8 (4.0–11.6)> the basis of those literature data, an introduction of 6 4.7 (2.8–8.0) o-OCH3, m-Cl, m-CF3 and o-F substituents should enhance the 5-HT1A in vitro activity of respective 8 3.1 (1.8–5.3) analogues of compound 4. This effect was ob- 9 9.1 (5.9–14.1) served only for m-CF3 derivative (9, Ki =53nMvs. Ketanserin 0.14 (0.07–0.20) 4, Ki = 70 nM ) whereas o-OCH3 and m-Cl groups produced a slight decrease in the 5-HT1A affinity of = ED# – the dose inhibiting the head twitches in mice by 50%. compounds 5 and 6 (Ki = 92 and 96 nM, respec- > Confidence limits (90%) given in parenthesis. The investiga- tively). Unexpectedly, compound 7 with o-F sub- ted compounds (ip) were administered 60 min before (±)-DOI stituent was six times less potent than the unsubsti- tuted phenylpiperazine 4. It the case of p-F ana- It was found previously that the LLR in rats logue (8) a substantial decrease in the 5-HT1A induced by 8-OH-DPAT (5-HT1A receptor agonist) affinity was observed, what is in agreement with is mediated by postsynaptic 5-HT1A receptors [1], previously published data, that substituents in para therefore, in order to determine postsynaptic 5-HT1A position (with different electronic properties) caused receptor agonistic effect of 9 (5-HT1A receptor unfavorable steric interactions with the 5-HT1A re- ligand) its ability to induce LLR in rats was tested, ceptor binding site [14]. whereas its 5-HT1A antagonistic activity was as- With regard to the 5-HT2A receptors, the o-OCH3 sessed via inhibition of that symptom produced by group exerted the most negative effect on the affi- 8-OH-DPAT in rats. Compound 9 at doses of 10 nity, however the presence of m-Cl and p-F sub- and 20 mg/kg given alone did not produce any ef- stituents enhanced it (6, Ki =17nMand8, Ki =14 fect in rats (data not shown); at the same time, it nM, respectively). These results are in line with the (10 and 20 mg/kg) inhibited the 8-OH-DPAT-indu- recently published investigation in the series of ced LLR in rats by 61 and 79% (p < 0.01), respec- 1,2,3-benzotriazin-4-one-arylpiperazine derivatives tively. A well-known 5-HT1A receptor antagonist [5]. On the contrary, affinity of m-CF3 derivative WAY 100635 [7], used as a standard compound, (9) was decreased by two times in comparison to administered at a dose of 0.1 mg/kg reduced the parent compound 4, whereas the respective m-CF3- LLR evoked by 8-OH-DPAT by 90% (p < 0.01). -phenylpiperazine analogue in the above-cited study Thus compound 9 may be regarded as the antago- of Caliendo et al. [5] was the most active. Never- nist of postsynaptic 5-HT1A receptors. theless, the dual activity of compound 9 was good A decrease in mice body temperature induced enough to test it further in in vivo experiments for by 8-OH-DPAT was previously described as the both receptors. effect connected with stimulation of presynaptic Further phase of our investigation was concen- 5-HT1A receptors [10] and sensitive to WAY 100635 trated on in vivo effect of four selected compounds [7]. In our studies, the maximum hypothermic ef- which demonstrated the highest affinity for 5-HT2A fect in mice (–1.4 ± 0.2°C, p < 0.01) evoked by (4, 6, 8 and 9) and for 5-HT1A receptors (9). The 8-OH-DPAT (5 mg/kg) has been observed at 15 min ability of these compounds to reduce head twitches after its administration and was completely abol- in mice, observed after administration of (±)-DOI, ished by WAY 100635 (0.1 mg/kg). Compound 9, a 5-HT2A agonist [6], was regarded as a 5-HT2A an- like 8-OH-DPAT, given alone at doses of 10–20 tagonistic activity. Compounds 4, 6, 8 and 9 as well mg/kg produced hypothermia in mice; the maxi-

ISSN 1230-6002 399 H. Byrtus, M. Paw³owski, B. Duszyñska, A. Weso³owska, E. Chojnacka-Wójcik, A.J. Bojarski mal decrease in body temperature (by 1.0 ± 0.1°C, to rat brain membranes in vitro by 1-phenylpiperazi- p < 0.01) was observed 30 min after administration nes. Biochem. Pharmacol., 1980, 29, 833–835. of both doses of 9. The hypothermia evoked by 9 9. Goodson L.H., Honigberg J.L., Lehman J.L., Burton (10 mg/kg) was blocked by WAY 100635 (p < 0.01, W.H.: Potential growth antagonists. I. Hydantoins and disubstituted glycines. J. Org. Chem., 1960, 25, data not shown), therefore, it may be concluded 1920–1924. that 9 can be a presynaptic 5-HT1A receptor agonist. 10. Goodwin G.M., De Souza R.J., Green A.R.: The phar- The obtained results indicate that compound 9 macology of the hypothermic response in mice to 8- containing m-CF3 substituent in phenyl ring, with hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). satisfactory 5-HT1A/5-HT2A receptor affinity, is A model of presynaptic 5-HT function. Neurophar- partial agonist of (agonist of pre- and antagonist of macology, 1985, 24, 1187–1194. 11. Huff J.R., King S.W., Saari W.S., Springer J.P., Martin postsynaptic) 5-HT1A receptors and antagonist of 5-HT receptors which makes it an interesting po- G.E., Williams M.: Bioactive conformation of 1- 2A arylpiperazines at central serotonin receptors. J. Med. tential psychotropic substance. Further studies with Chem., 1985, 28, 945–948. this group of derivatives are currently in progress. 12. Lopez-Rodriguez M.L., Morcillo M.J., Fernandez E., Porras E., Orensanz L., Beneytez M.E., Manzanares Acknowledgment. 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