title: Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation.
abstract: In general, 3alpha-(diphenylmethoxy)tropane (benztropine)-based dopamine uptake inhibitors do not demonstrate cocaine-like pharmacological activity in models of psychostimulant abuse and have been proposed as potential medications for the treatment of cocaine addiction. However, several (S)-2-carboalkoxy-substituted-3alpha-[bis(4-fluorophenyl)methoxy]tropane analogues were discovered to stimulate locomotor activity and substitute in subjects trained to discriminate cocaine, suggesting a role of the 2-position substituent in mediating these cocaine-like actions. Herein, we describe the synthesis of a series of novel N- and 2-substituted-3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues. Most of these analogues demonstrated high affinity binding to the dopamine transporter (DAT; K(i) = 1.8-40 nM), and selectivity over the other monoamine transporters and muscarinic M(1) receptors. When the (S)-2-carboalkoxy substituent was replaced with (S)-2-ethenyl, the resulting analogue 11 demonstrated the highest DAT binding affinity in the series (K(i) = 1.81 nM) with DAT selectivity over serotonin transporters (SERT; 989-fold), norepinephrine transporters (NET; 261-fold) and muscarinic receptors (90-fold). When the 4'-F groups of compounds 5 (K(i) = 2.94 nM) and 8 (K(i) = 6.87 nM) were replaced with 4'-Cl in the (S)-2-carboalkoxy series, DAT binding affinities were slightly reduced (K(i) = 12.6 and 14.6 nM for 6 and 7, respectively), yet inhibition of dopamine uptake potency remained comparably high (IC(50) range = 1.5-2.5 nM). Interestingly, the 4'-Cl analogue (+/-)-6 substituted less in rats trained to discriminate cocaine than the 4'-F analogue (+/-)-5. These studies demonstrate that manipulation of the 2-, N-, and 3-position substituents in the 3alpha-(diphenylmethoxy)tropane class of dopamine uptake inhibitors can result in ligands with high affinity and selectivity for the DAT, and distinctive in vivo pharmacological profiles that cannot be predicted by their effects in vitro.
authors.affiliation: Medicinal Chemistry and Psychobiology Sections, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, DHHS, Baltimore, Maryland 21224, USA.
authors.forename: Mu-Fa
authors.initials: MF
authors.lastname: Zou
authors.forename: Jianjing
authors.initials: J
authors.lastname: Cao
authors.forename: Theresa
authors.initials: T
authors.lastname: Kopajtic
authors.forename: Rajeev I
authors.initials: RI
authors.lastname: Desai
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Katz
authors.forename: Amy Hauck
authors.initials: AH
authors.lastname: Newman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D043643:Receptor, Muscarinic M1; D050486:Serotonin Plasma Membrane Transport Proteins; D014326:Tropanes; D003042:Cocaine