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1,3,8- and 1,3,7-Substituted Xanthines: Relative Potency As Adenosine Receptor Antagonists at the Frog Neuromuscular Junction A.M

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1,3,8- and 1,3,7-Substituted Xanthines: Relative Potency As Adenosine Receptor Antagonists at the Frog Neuromuscular Junction A.M Br. J. Pharmacol. (1989), 96, 211-219 1,3,8- and 1,3,7-substituted xanthines: relative potency as adenosine receptor antagonists at the frog neuromuscular junction A.M. Sebastido & J.A. Ribeiro Laboratory of Pharmacology, Gulbenkian Institute of Science, 2781 Oeiras, Portugal 1 The ability of 1,3,8-substituted xanthines (1,3-dipropyl-8-(4(2-aminoethyl)amino) carbonylmethyloxyphenyl)xanthine (XAC), 1,3-dipropyl-8(4-carboxymethyloxyphenyl)xanthine (XCC), 1,3-dipropyl-8-2-amino-4-chlorophenyl)xanthine (PACPX), 1,3-dipropyl-8-cyclo- pentylxanthine (DPCPX), 1,3-diethyl-8-phenylxanthine (DPX) and 8-phenyltheophylline (8-PT)), of 1,3,7-substituted xanthines (1-propargyl-3,7-dimethylxanthine (PGDMX) and caffeine), and of a 3- substituted xanthine (enprofylline) to antagonize the inhibitory effect of 2-chloroadenosine (CADO) on the amplitude of nerve-evoked twitches was investigated in innervated sartorius muscles of the frog. 2 All the 1,3,8-substituted xanthines, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right, in a near parallel manner the log concentration-response curve for CADO. Linear Schild plots with slopes near to unity at concentration-ratios less than 14 were obtained for XAC, XCC, DPCPX, DPX and 8-PT. 3 The order of potency of the 1,3,8-substituted xanthines as antagonists of the effect of CADO was XAC (Ki = 23 nM) 2 DPCPX (35 nM) > 8-PT (200 nm) 2 DPX (295 nM) > XCC (1905 nM) 2 PACPX (2291 nM). No correlation was found between the potency of these xanthines as antagonists of the adenosine receptor at the frog neuromuscular junction and their reported potency as antagonists of the A1- or A2-adenosine receptors. 4 The 1,3,7-substituted xanthines, PGDMX and caffeine, in concentrations virtually devoid of effect on neuromuscular transmission, also caused parallel shifts to the right of the log concentration-response curves for CADO, but were less potent than the 1,3,8-substituted xanthines. PGDMX was more than 20 times more potent than caffeine. 5 Enprofylline in concentrations up to 100pM did not antagonize the inhibitory effect of CADO on neuromuscular transmission. 6 It is concluded that the antagonist profile of the adenosine receptor mediating inhibition of transmission at the frog neuromuscular junction is different from the antagonist profile of the A1- and A2-adenosine receptors. Introduction Two subtypes of xanthine-sensitive adenosine recep- receptors the agonist profile is reversed, i.e. tors have been postulated on biochemical grounds: NECA > CADO > L-PIA, CHA (e.g. Daly et al., A1 (R.) operating inhibition and A2 (R.) operating 1981). stimulation of adenylate cyclase (Van Calker et al., The adenosine receptor mediating the adenosine- 1979; Londos et al., 1980). These two subtypes of induced presynaptic inhibition of neuromuscular adenosine receptor have different pharmacological transmission in the innervated frog sartorius muscle profiles for agonists. At Al-adenosine receptors the has an agonist profile with L-PIA, CHA and NECA order of agonist potency is L-N6-phenylisopro- being of similar potency and more potent than pyladenosine (L-PIA), N6-cyclohexyladenosine CADO (Ribeiro & Sebastiao, 1985). The observation (CHA) > 2-chloroadenosine (CADO) > 5'-N-ethyl- that this agonist proffle is similar to that described carboxamide adenosine (NECA). At A2-adenosine for the adenosine receptors mediating a decrease in © The Macmillan Press Ltd 1989 212 A.M. SEBASTIAO & JA. RIBEIRO neurotransmitter release in most of the peripheral 2-chloroadenosine (CADO), were obtained first in and central synapses, but is different from the the absence of the antagonist. CADO was then agonist profile of both A1- and A2-adenosine recep- washed out and the preparation equilibrated with tors, prompted the hypothesis that the adenosine the antagonist for at least 40min. A second cumula- receptor-mediating presynaptic inhibition of synaptic tive concentration-response curve for CADO, now in transmission by adenosine belongs to a third (A3) the presence of the antagonist, was then performed. subtype of xanthine-sensitive adenosine receptors After a washing out period of 60-90min, a third (Ribeiro & Sebastiao, 1986). Agonist potency can, cumulative concentration-response curve for CADO however, be influenced by factors unrelated to recep- again in the absence of the antagonist was finally tor type (see e.g. Kenakin, 1987), which complicates obtained. The usual procedure was to average the receptor classification on the basis of different responses in the same experiment to the same con- agonist profiles. centration of CADO in the absence of antagonist, to Xanthine derivatives with some antagonist selec- obtain the control responses to CADO. Whenever tivity for A1- and A2-adenosine receptors have the control effect of CADO after washing out the recently been developed (e.g. Daly et al., 1987). In the antagonist was smaller than the effect of the same present work we have studied the relative potency of concentration of CADO before exposure to. the some of the substituted xanthines as antagonists of antagonist, we considered that the action of the the adenosine receptor that mediates the presynaptic antagonist was not fully reversible; in these cases the inhibition of neuromuscular transmission in the post-control concentration-response curve for innervated sartorius muscle preparation of the frog. CADO was not included in the calculations. This Several 1,3,8- and 1,3,7-substituted xanthines were was frequently observed in the experiments using the used. CADO was used as the agonist because this highest concentration (100nM) of 1,3-dipropyl-8-(4- adenosine analogue is a full agonist of the adenosine (2-aminoethyl)amino) carbonylmethyloxyphenyl)- receptor in the frog innervated sartorius preparation xanthine (XAC), but not in the experiments using and is easily washed out (Ribeiro & Sebastiao, 1985). other xanthines. A brief account of some of the results has already The concentration of CADO producing 35% been published (SebastiAo & Ribeiro, 1988a). decrease in the amplitude of nerve-evoked twitches was calculated in each experiment by regression analysis of the linear part of the log concentration- Methods response curves for CADO. The concentration of CADO causing 35% effect is near its EC50 value The experiments were carried out at room tem- since the maximal effect of CADO (determined from perature (22-250C) on innervated sartorius muscles the double reciprocal plot of the averaged of the frog (Rana ridibunda) (see e.g. Kharkevich, concentration-response curves for CADO, n = 51) 1986). The preparations were set up in a 25 ml organ was 65% decrease in twitch amplitude. The ratios bath through which the solutions flowed contin- between equi-active concentrations (CR) of CADO uously with the aid of a roller pump. The solutions (causing 35% effect) in the presence and in the were changed by transferring the inlet tube of the absence of the antagonist were used in the Schild pump from one flask to another. The flow rate was equation (Arunlakshana & Schild, 1959) 25 ml min- during the first 2 min after changing the solutions and 5mlmin-1 until the next changeover log(CR - 1) = n log[B]- log Ki of solutions. Rectangular pulses of 0.1 ms duration where [B] is the molar concentration of antagonist and supramaximal voltage were applied to the nerve and Ki the equilibrium dissociation constant of the once every 5 s. The twitch responses to nerve stimu- antagonist for the receptor. pA2 values were deter- lation were recorded isometrically at a resting mined on the abscissae intercept of the regression of tension of 50 mN with a Sanborn transducer and dis- log(CR - 1) upon log[B]. Where the regression was played on a Hewlett-Packard recorder. The bathing linear and the slope (n) approximated to unity, the solution (pH 7.0) contained (mM): NaCl 117, KCI 2.5, Ki value was taken as the negative antilog of the pA2 CaCl2 1.8, MgCl2 1.2, NaH2PO4 1, Na2HPO4 1. value. The average nerve-evoked twitch amplitude in the control bathing solution for the experiments described in this paper was 22 + 1.3 mN. Drugs Concentration-response curves and Schild regressions Drugs used were: caffeine, 2-chloroadenosine (CADO) (Sigma); 1,3-diethyl-8-phenylxanthine In each experiment the cumulative concentration- (DPX), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)- response curves to the adenosine receptor agonist, xanthine (PACPX), 1,3-dipropyl-8-cyclopentylxan- XANTHINES AT THE NEUROMUSCULAR JUNCTION 213 H H Xanthine 0 0 H3C ~ H N N 7/y N<33 N CH3 C2H5 8-PT DPX JH2 0 H7C3 ll H -Cl N'N N C3H7 PACPX DPCPX 0 H7C3 H7C3 IN F|IH - OCH2COOH C3H7 XAC xCC Figure 1 Structures of the 1,3,8-substituted xanthines. The structure of xanthine is illustrated at the top. 8-PT: 8-phenyltheophylline; DPX: 1,3-diethyl-8-phenylxanthine; PACPX: 1,3-dipropyl-842-amino4-chlorophenyl)- xanthine; DPCPX: 1,3-dipropyl-8-cyclopentylxanthine; XAC: 1,3-dipropyl-8-(4-((2-aminoethyl)amino)- carbonylmethyloxyphenyl)xanthine; XCC: 1,3-dipropyl-844-carboxymethyloxyphenyl)xanthine. thine (DPCPX), enprofylline, 8-phenyltheophyline Bethesda, U.S.A.). 8-PT and DPX were made up into (8-PT) (R.B.I.); 1,3-dipropyl-844-((2-aminoethyl) 10mm and 50mm stock solutions, respectively, in amino) carbonylmethyloxyphenyl)xanthine (XAC), 80% methanol/20% M NaOH (v/v); PACPX and 1,3-dipropyl-8-(4-carboxymethyloxyphenyl)xanthine DPCPX were made up into 10mM and 5mM stock (XCC) and 1-propargyl-3,7-dimethylxanthine solutions, respectively, in 99% dimethylsulphoxide (PGDMX) were kindly supplied by Drs J.W. Daly (DMSO)/1% M NaOH (v/v); XAC and XCC were and K.A. Jacobson (National Institute of Health, made up into 80M and 2.5 mm stock solutions, 214 A.M. SEBASTIAO & J.A. RIBEIRO A a b c 80r 80 - 80r a) CA a) 40p 40.
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