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RTI-4793-14, a New Ligand with High Affinity and Selectivity For

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RTI-4793-14, a New Ligand with High Affinity and Selectivity For SYNAPSE 16:59-65 (1994) RTI-4793-14, a New Ligand With High Affinity and Selectivity for the ( +)-MK801-Insensitive [3H]1 -[ 1 -( 2- thienyl)cyclohexyl]piperidine Binding Site (PCP Site 2) of Guinea Pig Brain CARL B. GOODMAN, D. NIGEL THOMAS, AGU PERT, BETSEY EMILIEN, JEAN L. CADET, F. IVY CARROLL, BRUCE E. BLOUGH, S. WAYNE MASCARELLA, MICHAEL A. ROGAWSKI, SWAMINATHAN SUBRAMANIAM, AM) RICHARD B. ROTHMAN Clinical Psychopharmacology Section, NIDMNIH Addiction Research Center, Baltimore, Maryland 21224 (C.B.G., B.E., J.L.C., R.B.R.); Biological Psychiatry Branch, NZMH (D.N.T., A.P.) and Neuronal Excitability Section, Epilepsy Research Branch, NINDS (M.A.R., S.S.), NIH, Bethesda, Maryland 20892; and Chemistry and Life Sciences, Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194 (F.I.C., B.E.B., S.W.M.) KEY WORDS Phencyclidine receptor, RTI-4793-14, PCP, Biogenic amine reuptake carrier, ( + )-MK801, Guinea pig brain ABSTRACT L3HlTCP, an analog of the dissociative anesthetic phencyclidine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one that is MK-801 sensitive and one that is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors, whereas the MK-801-insensitive site (PCP site 2) may be associated with biogenic amine transporters (BAT).Although several “BAT ligands” are known that bind selectively to PCP site 2 and not to PCP site 1 (such as indatraline), these corn- pounds have low affinity for site 2 (K, values > 1 pM). Here we demonstrate that the novel pyrrole RTI-4793-14 is a selective, high affinity ligand for PCP site 2. We deter- mined the IC5, values of RTI-4793-14 and several reference compounds [PCP, (+ )-MK801 and indatraline] for PCP site 1(assayed with [3H](+)-MK801),PCP site 2 (assayed with [3H]TCP in the presence of 500 nM (+)-MK801) and a variety of BAT-related measures ([3H]CFT binding to the DA transporter, [3H]nisoxetine binding to the norepinephrine transporter, [3H]dopamine uptake, [3Hlserotonin uptake). In addition, we determined the ability of RTI-4793-14 to block NMDA responses in cultured hippocampal neurons under voltage clamp. (+)-MK801 had high affinity for PCP site 1 (4.6 nM) and potently inhibited NMDA-induced responses, but was much less potent in the BAT-related mea- sures (IC,,s > 10 pM). PCP had high affinity at PCP site l (IC50= 92 nM) and PCP site 2 (1C5, = 117 nM), and was moderately potent in all BAT-related measures except [3H]nisoxetine binding. Indatraline was potent in BAT-related measures (IC,,s, 2 to 5 nM), but weak in other measures (ICs0s > 1 pM). In contrast, RTI-4793-14 had high affinity for PCP site 2 (38 nM), low affinity for PCP site 1 (> 36 pM), moderate IC5,s for all BAT-related measures, and negligible activity at NMDA receptors. Viewed collec- tively, these data indicate that RTI-4793-14 binds with high affinity and selectivity to PCP site 2 and provide further support for an association between PCP site 2 and the BATS. D 1994 WiIey-Liss, Inc.* INTRODUCTION [3H]1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and [3H]MK-801 have been extensively used to label the Received June 21,1993; accepted in revised form August 26,1993. Address reprint requests to Carl B. Goodman, Clinical Psychopharmacology binding site associated with NMDA re- Section, NIDA, NIH, Addiction Research Center, Box 5180, Baltimore, MD ceptors (PCP site 1).However, C3HlTCP also binds to a 21224. 0 1994 WILEY-LISS, INC. *This article is a US Government work and, as such, is in the public domain in the United States of America. 60 C.B.GOODMAN ET AL. site that is insensitive to MK-801 (PCP site 2) and HCl, pH 8.0 (10 mhrain). The homogenate was centri- [3H]TCP in the presence of MK-801 can be used to label fuged at 37,000 x g for 10 min, and the pellet was this site. Several lines of evidence suggest that this site washed by resuspension in the same volume of buffer may be associated with biogenic amine transporters followed by recentrifugation. The pellets were resus- (Rothman et al., 1989; Akunne et al., 1991; Akunne et pended in an equal volume of 5 mM Tris-HC1, pH 8.0, al., 1992; Rothman et al., 1992). First, PCP, which in- and the concentration was adjusted to 50 mM by the hibits the reuptake of dopamine (DA) and serotonin addition of 1 M Tris-HC1, pH 8.0. The homogenate was (5-HT) (Smith et al., 1977), has high affinity for site 2, centrifuged for 10 min at 37,000 x g. The pellets were whereas (+ I-MK801, which is a very weak DA reuptake then washed three times by resuspension and centrifu- blocker (Snell et al., 1988)) does not bind to this site. gation using 50 mM Tris HC1, pH 8.0. The final pellets Second, as reported for the guinea pig (Rothman et al., were resuspended in the Tris-HC1 buffer (0.5 mlibrain), 1989) and human brain (Akunne et al., 19911, high af- pooled and 1ml aliquots were distributed to microfuge finity serotonergic (fluoxetine) and dopaminergic tubes, which were stored at -80°C for assay. Mem- (GBR12909 and BTCP) reuptake inhibitors bind selec- branes for the [3H]nisoxetine assay were prepared as tively to site 2. Third, fluoxetine, GBR12909, and BTCP described (Rothman et al., 1993). bind nearly irreversibly to PCP site 2 consistent with a For [3H12~-carbomethoxy-3p-(4-fluorophenyl)tro- high affinity interaction (Akunne et al., 1991). Fourth, pane (CFT, WIN35,428) binding assays (see below), MPTP-induced lesions of the dopaminergic innervation male Sprague-Dawley rats (200-300 g) (Charles River) to the caudate nucleus decrease [3H]TCP binding in were anesthetized with C02 gas and decapitated. Stri- this region (Akunne et al., 1992). The latter observation ata were dissected using glass manipulators, placed in suggests a partial presynaptic localization for at least small plastic containers, and then allowed to freeze by some of these sites. placing the container in dry ice. Striata collected in this Based upon the association of PCP site 2 with BATs, way were stored at -80" C. On the day of the assay, drugs with high affinity for PCP site 2 might be ex- each striatum was placed in ice-cold binding buffer (BB: pected to inhibit the reuptake of biogenic amines. In 55.2 mM sodium phosphate buffer, pH 7.4, 5 ml per the course of studying the interaction of a series of caudate) and homogenized while still frozen with a pyrroles with PCP binding sites, we observed that Polytron. The homogenate was centrifuged for 10 min (2RS,3aSR,8bRS)-1,2,3,3a,4,8b-hexahydro-2-benzyl-l-at 30,000 x g, and the pellet was resuspended in an methylindeno-[1,2-blpyrroleresorcylate (RTI-4793-14) equal volume of BB. The homogenate was recentri- was a potent and selective ligand for PCP site 2 (Carroll fuged, and the pellet was resuspended in an equal vol- et al., in press). The availability of this compound has ume of BB. An aliquot was saved for determination of enabled us to obtain further evidence supporting the protein (0.5 ml), and the remaining homogenate was concept that PCP site 2 is associated with BATs. brought up to a final volume of 50 mustriaturn using ice-cold BB. Typical final protein concentrations, deter- MATERIALS AND METHODS mined with the method of Lowry et al., (19511, were 100 Preparation of membranes pg/ml. Initial experiments showed that at these protein Since PCP site 1and PCP site 2 are readily measured concentrations, the specific binding was directly pro- in guinea pig brain membranes (Rothman et al., 1989, portional to protein and that < 10% of the radioligand 1992),the present study was conducted using this prep- was bound (data not shown). Aliquots of membranes aration. Large batches of frozen membranes were pre- were then used in the radioligand binding assays (see pared with minor modifications of published proce- below). dures (Rothman et al., 1989). Frozen guinea pig brains with cerebellum (20-30) were thawed for 15 min and homogenized with a Polytron in ice-cold 5 mM Tris- Binding assays The [3H]TCP binding assay for PCP site 2 was con- ducted with minor modifications of published protocols Abbreviations (Rothman et al., 1989). Briefly, 12 x 75 mm polysty- rene test tubes were prefilled with 100 pl of [3HlTCP(2 BTCP benzo[blthiophenylcyclohexylpiperidine CFT WIN35,428 2~-carbomethoxy-3~-(4-fluorophenyl)tropanenM final concentration) in a protease inhibitor/ GBR12909 l-[2-[bis(4-fluorophenyl)methoxylethyl]-4- antioxidant cocktail (PIC) containing 5,000 nM (+)- 13-phenyl-propyllpiperazine MK801, 100 pl of distilled H,O or drug (in distilled Indatraline (LU19-005)( f )-trans-3-(3,4-dichlorophenyl)-N- methyl-1-indanamine H,O), 50 pl of buffer (5 mM Tris-HC1, pH 8.01, and 750 ( + )-MK801 (+ )-5-meth~l-l0.11-dih~dro-5H-dibenzola.dl-p1 of membrane (0.5-1.0 mg/ml protein, in 5 mM Tris- cyclohepten-5,lO-iminemaleate (+)-dizocilpine HC1, pH 8.0). The (+I-MK801 (500 nM final concentra- RTI-4793-14 (2RS,3aSR,8aRS)-1,2,3,3a,8,8a-Hexahydro-2-tion) was included to block I3H1TCP binding to PCP site benzyl-l-methylindeno-[l,2-blpyrrole resorcylate 1. The protease inhibitorlanti-oxidant cocktail was TCP 1-1 1-(2-thienyl)cyclohexyllpiperidine composed of 25 Fg/ml leupeptin, 25 pg/ml chymostatin, RTI-4793-14 61 0.1 mM ethylenediaminetetraacetic acid (EDTA), test drugs made up in buffer containing 1mg/ml bovine and 0.1 mM ethyleneglycol-bis-(P-aminoethyl-ether)- serum albumin, and 50 pl of buffer.
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