Oxygenated Analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as Potential Extended-Action Cocaine-Abuse Therapeutic Agents

Abstract

An investigation into the preparation of potential extended-release cocaine-abuse therapeutic agents afforded a series of compounds related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (1b) (GBR 12935 and GBR 12909, respectively), which were designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of [(3)H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to the benzene ring on the phenylpropyl moiety of 1a-1d resulted in a series of potent and selective ligands for the DAT (analogues 5-28). The hydroxyl groups were included to incorporate a medium-chain carboxylic acid ester into the molecules, to form oil-soluble prodrugs, amenable to "depot" injection techniques. The introduction of an oxygen-containing functionality to the propyl side chain provided ketones 29 and 30, which demonstrated greatly reduced affinity for the DAT and decreased potency in inhibiting the uptake of [(3)H]DA, and benzylic alcohols 31-36, which were highly potent and selective at binding to the DAT and inhibiting [(3)H]DA uptake. The enantiomers of 32 (34 and 36) were practically identical in biological testing. Compounds 1b, 32, 34, and 36 all demonstrated the ability to decrease cocaine-maintained responding in monkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to each other and both more potent in behavioral tests than the parent compound 1b. Intramuscular injections of compound 41 (the decanoate ester of racemate 32) eliminated cocaine-maintained behavior for about a month following one single injection, without affecting food-maintained behavior. The identification of analogues 32, 34, and 36, thus, provides three potential candidates for esterification and formulation as extended-release cocaine-abuse therapeutic agents.

Dual Probes for the Dopamine Transporter and σ1 Receptors: Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

“…By removing the 2,6-dimethyl substituents on the piperazine ring, high affinity ligands at both DAT and σ 1 , with lower lipophilicity than previously reported analogues, were obtained. Further reduction in lipophilicity was also achieved by placing a hydroxyl group on the terminal N-propylphenyl chain (19). Behavioral evaluation of 10, 11, and 19 is currently underway in animal models of cocaine abuse to assess if these compounds display cocaine-like actions and how they effect cocaine's actions, in these models.…”

“…The HBr salt was made by dissolving the free base in methanolic HBr and then recrystallizing from acetone/ether; mp 229.5-230.5°C; 1 propyl]diphenylamine 11 (0.53 g, 1.64 mmol) and 3,4-dichlorophenylacetic acid (0.56 g, 2.71 mmol). After coupling and reduction (0.43 g, 53%), the amine was converted to the HCl salt and was recrystallized from acetone; mp 221-224°C; 1 (19). A solution of 15 (750 mg, 2.27 mmol) in acetone (4.54 mL) was added to a stirred solution of 3-chloropropiophenone (556 mg, 3.30 mmol) in acetone (5.67 mL).…”

Probes for the dopamine transporter: New leads toward a cocaine‐abuse therapeutic—A focus on analogues of benztropine and rimcazole

“…On this line, a series of oxygenated analogues were prepared as well as their esterified pro-drugs for potential use as extended release agents. 120 Heterocycles, as well as differentially substituted aryl rings have also been used to replace one or both of the phenyl rings in the diphenyl ether moiety of GBR 12909. 114 For the most part, these modifications have been well tolerated at DAT.…”

Further Structure−Activity Relationship Studies on 4-((((3S,6S)-6-Benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Identification of Compounds with Triple Uptake Inhibitory Activity as Potential Antidepressant Agents

“…The rationale behind designing these compounds stems from the observation that in the GBR class of compounds such side chain extension via opening of epoxide led to development of potent molecules for DAT and SERT. 29 Regioselective ring-opening of different substituted (R)-styrene epoxides by the amine precursor 8 produced R-hydroxy compounds 9a, 9c and 9e. On the other hand, regioselective ring-opening of similar (S)-epoxides by the same amine precursor yielded S-hydroxy compounds 9b, 9d and 9f.…”