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Dextrorphan Binds to Opioid Receptors in Guinea-Pig Brain Membranes And

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Dextrorphan Binds to Opioid Receptors in Guinea-Pig Brain Membranes And Proc. Natl. Acad. Sci. USA Vol. 87, pp. 1629-1632, March 1990 Pharmacology Dextrorphan binds to opioid receptors in guinea-pig brain membranes and is an antagonist at opioid receptors in myenteric plexus (binding/guinea-pig ileum/levorphanol/stereoselectivity) AVRAM GOLDSTEIN AND ASHA NAIDU Department of Pharmacology, Stanford University, Stanford, CA 94305 Contributed by Avram Goldstein, December 11, 1989 ABSTRACT Dextrorphan (+)-tartrate, purified by re- LaRoche); [D-Ala,MePhe4,Gly-ol5]enkephalin (DAGO; Pe- peated crystallization to remove all traces of the enantiomer ninsula Laboratories) (2); trans-3,4-dichloro-N-methyl- levorphanol, binds to IL, 6, and K sites on guinea-pig brain N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide methane- membranes with lower affinities (by a factor of400-3200) than sulfonate (U50,488; Upjohn) (3); (-)-naloxone hydrochloride levorphanol. In the guinea-pig ileum myenteric plexus longi- (NAL; Endo Laboratories, New York); normorphine hydro- tudinal muscle preparation (GPI), dextrorphan, at 100-200 chloride (NOR) and (+)-naloxone hydrochloride (National ,uM, inhibits the electrically stimulated twitch, but this action Institute on Drug Abuse); N-methyl-D-aspartic acid (NMDA), is not blocked or reversed by naloxone; both (+)- and (-)- aminophosphonovalerate, norepinephrine (levarterenol), at- naloxone produce similar non-opioid twitch inhibition at com- ropine, and eserine (physostigmine) (Sigma). parable concentrations. At 10-20 jaM, dextrorphan' blocks and Preparation ofDEXp. [3H]LEV (Ro 1-5431/701, Hoffmann- reverses the twitch inhibition due to ,u and KWagonists, but the LaRoche; 17.4 Ci/mmol; 1 Ci = 37 GBq) was purified' by blockade can be overcome only partially by increasing the preparative reversed-phase HPLC (Waters, C18 AgBondaPak, agonist concentration. We conclude that dextrorphan is an 3.9 x 300 mm, isocratic 75% CH3CN in 0.01 M sodium opioid ligand with low affinity and with antagonist effect on tartrate, 1.5 ml/min, 0.6-ml fractions). To 1 g of DEX (+)- opioid receptors in the GPI. tartrate was added 106 cpm of the purified [3H]LEV. Just enough boiling water was added to bring the material into The opioid receptors are highly stereoselective. Levorphanol solution, and repeated recrystallizations were carried out in (LEV, 3-hydroxy-N-methylmorphinan) is a high-affinity ,- this manner by overnight storage at 4°C. As LEV (+)-tartrate selective agonist, whereas its enantiomer dextrorphan (DEX) is somewhat less soluble in water than DEX'(+)-tartrate, it apparently has about three orders ofmagnitude lower affinity was possible to eliminate most of the tracer LEV and with it, than LEV at opioid binding sites (1). However, when a chiral presumably, any contaminant LEV initially present. After compound is obtained by resolution of a racemic mixture, each recrystallization step the redissolved DEX was mea- chemical standards of purity could not exclude the presence sured by absorbance at 279 nm, and the [3H]LEV content'was of 1 part per 1000 of an undesired enantiomer. We therefore assessed by radioactivity measurement in a scintillation considered the possibility that LEV, contaminating the DEX counter. supplied by the manufacturer, might be responsible for the Binding Assays. These were conducted as described (1) apparent low-affinity binding of DEX and thus that the with guinea-pig brain membranes, in TB and KHB, using receptors do not recognize DEX at all. Accordingly, ultra- radioligands and competing ligands in assays highly selective pure DEX (DEXp) was prepared as described under Mate- for u, 8, and K opioid binding sites. In an experiment with rials and Methods. This compound proved to be indistin- mouse brain membranes, [3H]LEV was used to label primar- guishable from the commercial starting material (DEXC) in its ily ,u sites. Ki values were computed from competition curves binding to guinea-pig brain membranes in standard ,u, 5, and to obtain ligand selectivity profiles, as described (1). K assays in two buffer systems. In guinea-pig ileum myenteric Guinea-Pig Ileum Assay. The electrically stimulated GPI, plexus longitudinal muscle preparation (GPI), DEXC and mounted in KRB, was used as described (4, 5). Concentra- DEXp, at 100-200 ,M, were equipotent in inhibiting the tions of substances added to the bath were incremented twitch by a non-opioid mechanism. At 10-20,uM they were geometrically, usually by doublings, and IC50 or IC30 values equipotent in blocking or reversing twitch inhibition due to (concentrations of agonists causing 50% or 30%6 inhibition of opioid agonists.' twitch amplitude) were obtained by interpolation on semi- logarithmic plots. MATERIALS AND METHODS RESULTS Drugs and Reagents. Reagents were Baker analytical grade or equivalent. Tris-HCI buffer (TB, mM concentrations): 50, The amount oftracer LEV added initially to DEXC, at a molar pH 7.4. Krebs-Hepes buffer (KHB): NaCI 118, KCl 4.8, ratio of 1:54 million (Table 1, cycle 0), was far too little to CaC12 2.5, MgCl2 1.2, Hepes (N-2-hydroxyethyl piperazine- contribute any activity of its own in binding assays or the N'-2-ethanesulfonic acid, Research Organics) 25,' pH GPI. After the fourth recrystallization, the added LEV (and adjusted to 7.4 with NaOH. Krebs-Ringer buffer (KRB): therefore any LEV present initially as a contaminant of same as KHB with KH2PO4 1.2 and NaHCO3 25 instead of Hepes, and, in addition, glucose 11, choline chloride 0.02; Abbreviations: LEV, levorphanol; DEXC, commercial dextrorphan; mepyramine maleate (125 nM) were also present. KRB was DEXp, purified dextrorphan; GPI, guinea-pig ileum myenteric plexus longitudinal muscle preparation; DAGO, [D-Ala2,MePhe4,Gly- bubbled constantly with 5% CO2 in 02 at 37°C to maintain pH o15]enkephalin; NAL, (-)-naloxone hydrochloride; NOR, normor- 7.4. phine hydrochloride; NMDA, acid; BREM, Drugs and suppliers are as follows: dextrorphan (+)-tartrate bremazocine; DPDPE, [D-penicillamine,N-meth~yl-D-asparticD-penicillamineSjenkepha- (DEX) and levorphanol (+)-tartrate (LEV) (Hoffmann- lin. 1629 Downloaded by guest on September 23, 2021 1630 Pharmacology: Goldstein and Naidu Proc. Natl. Acad Sci. USA 87 (1990) Table 1. Removal of added [3H]LEV (17.4 Ci/mmol) from DEX LEV by repeated recrystallization of the (+)-tartrate salt A ----- - ------ I - - -- -- -- ------ K. 8 Purification Cycle LEV, pmol DEX, mmol LEV/DEX factor 0 43.2 2.35 1.84 x 10-8 1.0 DEXc 8 . 1 5.63 1.12 5.03 x 10-9 3.7 2 0.850 0.692 1.23 x 10-9 15. 3 0.0958 0.315 3.04 x 10-10 61. L K 8 DEX 4 0.0157 0.191 8.22 x 10-11 220. p g---L-.-. -K-.------- 8 Tracer LEV was added to DEXC tartrate and repeated recrystal- lizations were carried out. Residual [3H]LEV and DEX in each supernatant were determined by radioactivity measurement and l absorbance at 279 nm, respectively. The final product was called -10 -9 -8 -7 DEXp. DEXC) had been reduced, relative to DEX, by a factor of 220 -7 -6 -5 -4 (Table 1, cycle 4). We then compared DEXp (the material from the fourth LOG Ki with DEXC in the binding assay and the bioassay. Fig. cycle) FIG. 2. Ligand selectivity profiles of LEV, DEXC, and DEXp. 1 shows that the crude and purified ligands competed iden- Data are log(K,) values, computed from IC50 in standard binding tically for LEV binding sites in mouse brain membranes. Fig. assays with guinea-pig brain membranes, as described (1). Radioli- 2 presents the ligand selectivity profiles (1) of LEV, DEXc, gands were [3H]DAGO (for IL), [3H]DPDPE (for 8), and [3H]BREM and DEXp in guinea-pig brain membranes using standard , displaced by U50,488 (for K) in a paired-tube procedure (1). Note 8, and K binding assays. Again, the affinities of DEXC and different abscissa scales for LEV (upper) and DEX (lower). Each DEXP were the same. Thus, it is evident from both figures assay was carried out in both TB (solid lines) and KHB (broken sites could not lines), in at least three independent experiments. As documented that the affinities of DEXC for opioid binding elsewhere (1), SEM for each log (Kj) was -0.1 log unit, too small to be due to trace contamination by LEV. shown effectively here. The ligand selectivity profiles ofLEV and DEX were quite be similar except for the large difference in affinity at each ofthe concentrations (>400 IAM) NAL itself, and also its enantio- three sites. Interestingly, however, the actual K, ratios mer (+)-NAL, inhibited the twitch (not shown). (DEXC/LEV) were significantly different at the three types of In view of the findings ofChoi et al. (6) that dextrorotatory sites-3200 and 2500 at ,A 2500 and 1000 at 8, 790 and 400 at opiates block NMDA receptors, we considered the possibil- K (data for TB and KHB, respectively). These differences ity that the naloxone-resistant agonist effects seen here might provide additional evidence that the binding of DEXC could also be due to NMDA receptor-inhibition. However, neither not be due to LEV contamination. in the unstimulated nor in the stimulated GPI did NMDA In the GPI, DEXC and DEXp were tested on six strips. No itself have any effect (to 400 ,uM), nor did the NMDA inhibition was seen until concentrations of 100-200 FM were antagonist aminophosphonovalerate (to 400 gM) inhibit the reached, and then both inhibited the twitch with essentially electrically stimyjated twitch. We conclude that NMDA the same IC50 (Table 2). Within-strip comparisons with NOR receptors, if present, do not mediate the electrically stimu- were computed in order to normalize for strip-to-strip sen- lated twitch and therefore that twitch inhibition by DEX is sitivity variations. DEXP was used in all subsequent exper- unrelated to NMDA receptors. iments on GPI, unless otherwise specified. As shown above, DEX, in the range 1-10 juM, clearly Typical GPI records are shown in Fig.
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