Carroll FI, Howard JL, Howell LL, Fox BS, Kuhar MJ. Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse. AAPS Journal. 2006; 8(1): E196-E203. DOI:  10.1208/aapsj080124

Correspondence to:
F. Ivy Carroll
Tel: (919) 541-6679
Fax: (919) 541-8868
Email: fic@rti.org

Received: October 25, 2005;  Accepted: December 23, 2005;  Published: March 24, 2006

Abstract

The discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacotherapies for treating cocaine addiction are presented. The studies are based on the hypothesis that a dopamine reuptake inhibitor is expected to partially substitute for cocaine, thus decreasing cocaine self-administration and minimizing the craving for cocaine. This type of indirect agonist therapy has been highly effective for treating smoking addiction (nicotine replacement therapy) and heroin addiction (methadone). To be an effective pharmacotherapy for cocaine addiction, the potential drug must be safe, long-acting, and have minimal abuse potential. We have developed several 3-phenyltropane analogs that are potent dopamine uptake inhibitors, and some are selective for the dopamine transporter relative to the serotonin and norepinephrine transporters. In animal studies, these compounds substitute for cocaine, reduce the intake of cocaine in rats and rhesus monkeys trained to self-administer cocaine, and have demonstrated a slow onset and long duration of action and lack of sensitization. The 3-phenyltropane analogs were also tested in a rhesus monkey self-administration model to define their abuse potential relative to cocaine. Based on these studies, 3β-(4-chlorophenyl)-2β-[3-(4’-methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected for preclinical development.

Keywords: RTI-336, dopamine transporter, cocaine abuse, pharmacotherapy, 3-aryltropanes

Introduction

Drug abuse, addiction, and dependence represent a major and increasing threat to public health. Cocaine abuse has been an epidemic in the United States since the introduction of crack in the mid-1980s. The 2003 National Survey on Drug Use and Health (NSDUH) estimated that 34.9 million Americans, aged 12 and older, have used cocaine at least once in their lifetime, that 5.9 million used cocaine in the past year, and that 2.3 million Americans are current users—some frequently, others occasionally (NSDUH report).¹ In 2002, the estimated number of cocaine-related emergency episodes totaled over 199 000.² While these numbers on use and cost show the magnitude of the drug abuse problem, the human suffering is incalculable. Illness, crime, domestic violence, reduced productivity, and lost opportunity are direct consequences of drug abuse. There is an increasing understanding that drug abuse is a physiologic disorder and that the need for medications for the treatment of drug abuse is tremendous. Even though several pharmacological agents have been tried on the basis of various hypotheses, none of the pharmacotherapeutic approaches has proven effective.^3-6 To address this critical deficiency, National Institute on Drug Abuse (NIDA) has made the development of an anticocaine medication a high priority.

In vitro studies have demonstrated that cocaine blocks the presynaptic uptake of dopamine, serotonin, and norepinephrine. However, it is the dopamine transporter (DAT) that is believed to be the critical recognition site for cocaine, mediating the behavioral and reinforcing effects that contribute to its abuse liability.^7-11 Numerous cocaine-discrimination and self-administration studies in laboratory animals support this conclusion.

A dopamine reuptake inhibitor would be expected to partially substitute for cocaine, thus decreasing cocaine self-administration and minimizing the craving for cocaine. This type of substitution pharmacotherapy has been highly effective for treatment of nicotine addiction (nicotine gum and patch) and heroin addiction (methadone). The development of a comparable drug for cocaine addiction would allow control of the behavior of the abuser until a strategy for long-term abstinence could be developed. We have discovered novel 3-phenyltropane analogs that are dopamine-selective reuptake inhibitors. It is hoped that one of these compounds will be useful as a medication for treating cocaine addicts without deleterious side effects.¹²

Over the last several years, we synthesized several 3-phenyltropane analogs and evaluated them for binding at the dopamine, serotonin, and norepinephrine transporters (DAT, 5-HTT, and NET, respectively). Forty-seven compounds showed selectivity for the DAT relative to the 5-HTT and NET, based on their relative IC₅₀ values.^12,13 The binding affinities of these compounds are compared with cocaine and 3-phenyltropane 2-carboxylic acid methyl ester (WIN 35,065-2) in Tables 1-4. The compounds possess either a 4-chloro or 4-methylphenyl group at the 3β-position of the tropane ring and have an ester, amide, isoxazole, oxadiazole, benzthiazole, benzimidazole, or thiazole group in the 2β-position. The 15 RTI compounds shown in Table 1 have various ester groups in the 2β position of the tropane ring. The affinity for the dopamine transporter varies from 0.96 nM for RTI-190 to 9.6 nM for RTI-145. The affinities for the ten 2β amides listed in Table 2 vary from 0.75 nM for RTI-227 to 6.95 nM for RTI-156. Note the very high DAT selectivity for RTI-147, RTI-214, and RTI-218. The affinities for the 2β-isoxazoles listed in Table 3 vary from 0.50 nM for RTI-334 to 8.7 nM for RTI-371. Table 4 compares the inhibition of radioligand binding at the dopamine, norepinephrine, and serotonin transporters to those of cocaine and WIN 35,065-2 for 6 different other 2β heterocyclic analogs. Together, these compounds possess sufficient structural diversity to provide considerable variation in physicochemical properties. Furthermore, given their close structural similarity to other RTI compounds with known behavioral activity (RTI-32, -55, -113, -121, and -130),^14,15 it was expected that these compounds would both cross the blood-brain barrier and possess behavioral activity.

Table 1. 3β-Phenyltropane 2-Ester Analogs Selective for the DAT

IC50, nM (Ki, nM) Compound RTI-4229- X R DA [3H]WIN 35,428 NE [3H]Nisoxetine 5-HT [3H]Paroxetine NE/DAa Ratio 5-HT/DA* Ratio Cocaine — — 89.1 3298 (1987) 1045 (95) 37 12 WIN 35,065-2 H CO2CH3 23 920 (554) 2000 (182) 40 87 190 Cl CO2C3H5 0.96 235 (142) 168 (15.3) 245 175 114 Cl CO2CH(CH3)2 1.40 778 (469) 1400 (122) 555 1000 193 CH3 CO2C3H5 1.68 644 (388) 1070 (92) 383 637 113 Cl CO2C6H5 1.98 2960 (1783) 2340 (212) 1490 1180 436 C6H5CH=CH CO2CH3 3.09 1960 (1181) 335 (31) 634 108 120 CH3 CO2C6H5 3.26 5830 (3512) 24,500 (2227) 1788 7515 150 CH3 CO2C4H7 3.74 4740 (2855) 2020 (134) 1267 540 204 Cl CO2C6H4CH3(2') 3.91 4780 (2880) 3770 (342) 1223 964 277 NO2 CO2C6H5 5.94 5700 (3434) 2910 (265) 960 490 430 C6H5(CH2)2C≡C- CO2CH3 6.28 1470 (886) 2182 (198) 234 348 117 CH3 CO2CH(CH3)2 6.45 1930 (1153) 6090 (554) 299 944 278 NO2 CO2CH(CH3)2 8.14 4100 (2170) 2150 (196) 504 264 205 CH3 CO2C6H4CH3(3′) 8.19 2130 (1283) 5240 (427) 260 640 203 Cl CO2C6H4CH3(3′) 9.37 2740 (1651) 2150 (196) 292 230 145 Cl CH2OCO2CH3 9.6 1480 (892) 2930 (266) 154 305 *Ratios of IC50 values.

Table 2. 3β-Phenyltropane 2β-Amide Analogs Selective for the DAT

IC50, nM (Ki, nM) Compound RTI-4229- X R DA [3H]WIN 35,428 NE [3H]Nisoxetine 5-HT [3H]Paroxetine NE/DA* Ratio 5-HT/DA* Ratio Cocaine — — 89.1 3298 (1906) 1045 (95) 37 12 WIN 35,065–2 H CO2CH3 23 920 (555.6) 2000 (182) 40 87 227 I 0.75 357 (275) 129 (11.7) 476 172 218 Cl CONCH3(OCH3) 1.19 8563 (5158) 1910 (174) 7200 1605 129 Cl CON(CH3)2 1.38 942 (568) 1079 (98.1) 683 781 147 Cl CON(CH2)4 1.38 3950 (2375) 12,400 (1120) 2862 8985 208 Cl 1.47 1080 (650) 2470 (225) 735 1680 186 CH3 CONCH3(OCH3) 2.55 442 (266) 3400 (309) 173 1333 214 Cl 2.90 8550 (5750) 88,800 (8070) 2948 30,620 217 Cl CONHC6H4OH(2') 4.78 31,000 (7867) 16,800 (1530) 6485 3515 215 Cl CON(C2H5)2 5.48 5530 9430 (857) 1009 1720 156 Cl CON(CH2)5 6.95 1750 (1054) 3470 (315) 252 499 *Ratios of IC50 values.

Table 3. 3β-Phenyltropane 2β-Isoxazole Analogs Selective for the DAT

IC50, nM (Ki, nM) Compound RTI-4229- X R DA [3H]WIN 35,428 NE [3H]Nisoxetine 5-HT [3H]Paroxetine NE/DA* Ratio 5-HT/DA* Ratio Cocaine — — 89.1 3298 (1986) 1045 (45) 37 12 WIN 35,065-2 H 23 920 (554) 2000 (182) 40 87 334 Cl —C2H5 0.50 120 (72) 3090 (281) 240 6180 165 Cl —CH3 0.59 181 (109) 572 (52) 307 970 171 CH3 —CH3 0.93 254 (153) 3820 (348) 273 4110 335 Cl —CH(CH3)2 1.19 954 (575) 2320 (216) 801 1950 177 Cl —C6H5 1.28 504 (304) 2420 (220) 394 1890 346 Cl —C6H4OCH3(4’) 1.57 762 (454) 5880 (535) 485 3740 176 CH3 —C6H5 1.58 398 (239) 5110 (465) 252 3230 354 CH3 —C2H5 1.62 299 (180) 6400 (582) 185 3950 347 Cl —C6H4F(4’) 1.86 918 (553) 7256 (660) 494 3901 386 CH3 —C6H4OCH3(4’) 3.93 756 (450) 4027 (380) 194 3600 336 Cl —C6H4CH3(4’) 4.09 1714 (1033) 5741 (522) 419 1171 366 CH3 —CH(CH3)2 4.5 2523 (1550) 42,900 (3900) 561 9533 345 Cl —C6H4CI(4’) 6.42 5290 (3790) >76 000 (6910) 824 >11,800 387 CH3 —C6H5F(4’) 6.45 917 (546) >100 000 (9400) 141 >15,400 337 Cl —C(CH3)3 7.31 6320 (3807) 36 800 (3346) 863 865 371 CH3 —C6H4CI(4’) 8.74 >100,000 (60 200) >100 000 (9090) >11 400 >11 400 *Ratio of IC50 values.

Table 4. 3β-Phenyltropane 2β-Heterocyclic Analogs Selective for the DAT

IC50, nM (Ki, nM) Compound RTI-4229- X R DA [3H]WIN 35,428 NE [3H]Nisoxetine 5-HT [3H]Paroxetine NE/DA* ratio 5-HT/DA* ratio cocaine 89 3298 (1986) 1045 (45) 37 12 WIN 35,065-2 H CO2CH3 23 920 (554) 2000 (182) 40 87 470 Cl 0.094 1590 (994) 1080 (98) 16 900 11 500 202 Cl 1.37 403 (250) 1120 (202.1) 294 818 451 CH3 1.53 476 (287) 7120 (647) 311 4700 439 CH3 1.57 1320 (795) >100 000 (>909) 841 >64 000 141 Cl 1.81 835 (503) 357 (32.4) 461 186 219 Cl 5.71 8560 (5157) 10 000 (909) 1500 1800 *Ratio of IC50 values.

In designing a potential pharmacotherapy for cocaine abuse, other pharmacological activities must also be considered. Evidence from both animal and human studies suggests that the pharmacokinetic and pharmacodynamic properties of cocaine are important in reinforcement.^16-22 It is well known that cocaine gets into the brain quickly after peripheral administration and produces a “high” in 1 to 4 minutes.^16-18 This relatively rapid onset of action apparently contributes to cocaine’s high efficacy as a reinforcer. Therefore, to minimize the possibilities of abuse, an ideal indirect agonist clinical candidate for cocaine addiction would have a slow onset of action. Samaha and Robinson²³ have demonstrated that differences in the rate at which cocaine is administered determine its ability to produce psychomotor sensitization and presumably the associated adaptation in the brains of rats. Thus, a clinical candidate should also show low sensitization. In addition, a long duration of action would be desirable. Volkow et al²⁴ used positron emission tomography (PET) studies to show that the rate of clearance for the relatively more potent methylphenidate was significantly slower than for cocaine and suggested that this could account for the much lesser abuse of methylphenidate than cocaine despite their otherwise similar pharmacological properties. Furthermore, in selecting a candidate for further development, it is preferable for the compound to be orally available and no more stimulatory than cocaine at peak doses. As a direct test of the compound's potential efficacy in humans, the compound should substitute for cocaine in animal models and should block cocaine self-administration in both rats and rhesus monkeys.

In order to identify 3-phenyltropane analogs that possessed pharmacological properties suitable for further consideration, the compounds listed in Tables 1 to 4 were first evaluated for locomotor activity in mice²⁵ and cocaine discrimination in rats; several compounds were also tested in in vitro toxicity assays listed in Table 5. The 5 compounds listed in Tables 6 and 7 showed the most favorable overall balance of pharmacological properties and toxicity results. It is interesting to note that all 5 compounds are 3β-phenyltropane 2β-1,2-(isoxazole) analogs (see Table 3 for structures). Examination of the data in Table 6 shows that cocaine produced its greatest stimulation in hour 1, and that by hour 3 the effect was gone. In contrast, all 2β-1,2-(isoxazoles) had their largest effect in hours 2 to 4. The ED₅₀ values for the 2β-1,2-(isoxazoles) ranged from 0.9 mg/kg for RTI-354 to 12.8 mg/kg for RTI-386. RTI-176 and RTI-354 produced greater stimulation than cocaine in their peak hours; RTI-177 had about the same stimulation as cocaine; and RTI-336 and RTI-386 were less stimulatory than cocaine.

All five 3β-(1,2-isoxazoles) selected for further evaluation showed full generalization to the cocaine cue (≥75% of rats choosing the cocaine lever), with the ED₅₀ values ranging from 0.82 mg/kg for RTI-354 to 11.0 mg/kg for RTI-386; the ED₅₀ for cocaine was 2.64 mg/kg.

3β-(4-Chlorophenyl)-2β(3-phenylisoxazol-5-yl)tropane (RTI-177), which possessed ED₅₀ values of 4.7 and 5.7 mg/kg in the locomotor activity and drug-discrimination test after oral administration (unpublished results, Carroll 2004) and also reduced cocaine self-administration after oral administration in a rat model of self-administration, was studied for its effect on cocaine self-administration in rhesus monkeys. Pretreatment intravenously (IV) with RTI-177 produced a dose-related reduction in cocaine self-administration in rhesus monkeys trained to self-administer cocaine (0.1 and 0.3 mg/kg) under a second-order schedule of IV drug delivery. The ED₅₀ was 0.11 mg/kg, which is an order of magnitude more potent than GBR 12909, which has an ED₅₀ of 1.29 mg/kg (Table 8).²⁶ PET neuroimaging studies revealed that the ED₁₀ doses of RTI-177 and GBR 12909 resulted in DAT occupancies below the threshold (<10%) of detection, whereas ED₅₀ doses resulted in DAT occupancies of 73% and 67%, respectively.²⁶ RTI-177 and GBR 12909 were substituted for cocaine in drug self-administration studies in order to characterize their reinforcing effects. Both RTI-177 and GBR 12909 reliably maintained drug self-administration at levels greater than those maintained by saline in all subjects (Figure 1). Moreover, the shape of the dose-effect curves resembled an inverted U-shape function typical of psychomotor stimulants. However, rates of responding were lower than those maintained by the training dose of cocaine (0.1 mg/kg/infusion) in 2 of 3 subjects substituted with GBR 12909 and in all 3 subjects substituted with RTI-177.

Figure 1. Self-administration of GBR 12909 and RTI-177. Response rates (responses per second) for GBR 12909 and RTI-177 as a function of drug dose under a second-order schedule of IV drug self-administration in individual subjects. The unbroken lines indicate mean rates of responding maintained by the training dose of cocaine (0.1 mg/kg/infusion). Dashed lines indicate the upper limit for responding during saline extinction. Each data point was determined on a single occasion and is the mean (±SD) of the last 5 sessions in a condition. Numbers in parentheses indicate percentage of DAT occupancy at doses that maintained peak rates of responding. Modified from Lindsey et al.26

In acute toxicity studies in male rats, 3β-(4-chlorophenyl)-2β-[3-(4’-methylphenyl)isoxazol-5-yl]tropane (RTI-336) possessed an LD₅₀ of 180 mg/kg after oral administration, compared with 49 mg/kg for RTI-177 (unpublished results, Howell 2005; Table 9). These results suggested that RTI-336 was a better candidate than RTI-177 for further preclinical development. Similar to RTI-177, RTI-336 showed oral activity in the locomotor activity and drug-discrimination test with ED₅₀s of 14.4 and 3.54 mg/kg, respectively. Of importance, RTI-336 showed very low sensitization relative to cocaine. RTI-336 reduced cocaine self-administration in a rat model of self-administration (unpublished results, Howell 2004), and in preliminary rhesus monkey studies, RTI-336 produced dose-dependent reductions in cocaine self-administration in 4 subjects and was equally effective at both maintenance doses of cocaine (0.1 and 0.3 mg/kg/injection). Food-maintained behavior was suppressed at the same doses of RTI-336 that suppressed cocaine-maintained behavior. Positron emission tomography (PET) imaging was conducted in the same subjects to determine the level of DAT occupancy associated with behaviorally-relevant doses of RTI-336. Doses of RTI-336 that reduced cocaine-maintained behavior by 50% (ED₅₀) resulted in 90% DAT occupancy for the group of 4 subjects. Daily food intake, body weight, and behavior were normal.

Conclusion

In summary, RTI-336 showed locomotor activity less than that of cocaine with no sensitization. It was orally active in both the locomotor assay in mice and drug discrimination tests in rats and possessed an excellent therapeutic ratio. RTI-336 reduced cocaine self-administration in both rat and rhesus monkey models and showed slow onset and long duration of action in rodent and monkey models. These preliminary studies in rhesus monkeys showed that RTI-336 was effective in suppressing cocaine self-administration at doses that had no obvious adverse behavioral effects. Varying the maintenance dose of cocaine had no influence on the effectiveness of drug pretreatments. There was no evidence of selective reductions in cocaine self-administration compared with food-maintained behavior. High levels of DAT occupancy were required to produce robust reduction in cocaine use.

Acknowledgments

This research was supported by the National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, grant No. DA05477.

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