ABSTRACT
A series of 3beta-naphthyltropane derivatives were synthesized and found to show high affinity at both the dopamine and serotonin transporter sites, leading to some of the most potent inhibitors known based on the tropane structure. Comparative molecular field analysis (CoMFA) models were developed for both dopamine and serotonin transporter binding data. These models provide insights into those factors that influence binding at the two transporters.
Subject(s)
Carrier Proteins/metabolism , Dopamine/metabolism , Membrane Glycoproteins/metabolism , Membrane Transport Proteins , Nerve Tissue Proteins , Serotonin/metabolism , Symporters , Tropanes/chemical synthesis , Animals , Binding, Competitive , Corpus Striatum/metabolism , Dopamine Plasma Membrane Transport Proteins , Frontal Lobe/metabolism , In Vitro Techniques , Models, Molecular , Norepinephrine/metabolism , Norepinephrine Plasma Membrane Transport Proteins , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins , Structure-Activity Relationship , Tropanes/chemistry , Tropanes/metabolismABSTRACT
A novel entry to tropane analogs of cocaine was developed on the basis of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine and serotonin (5-HT) transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3-position was directly bound to the tropane ring (as in WIN-35,428), and methyl or ethyl ketone moieties were present at the 2-position instead of the typical ester group. The series of analogs containing a 2-naphthyl group at the 3-position were most potent, with Ki values < 1 nM in binding to both dopamine and 5-HT transporters. Although the unsubstituted 2-naphthyl analog was nonselective at dopamine and 5-HT transport sites, other compounds were selective for either site. In general, compounds with relatively small substituents on the aromatic moiety (such as p-methyl or p-fluoro) were relatively selective for the dopamine transporters, while a p-isopropylphenyl derivative was selective for the 5-HT transport sites. This latter compound represents the first N-methyltropane derivative specific for 5-HT transporters. Resolution of two of the most significant analogs was achieved by HPLC on a chiral stationary phase; the active enantiomer of a 2-naphthyl analog exhibited Ki values of < 0.1 nM at both dopamine and 5-HT transporter sites.
Subject(s)
Carrier Proteins/metabolism , Cocaine/analogs & derivatives , Corpus Striatum/metabolism , Frontal Lobe/metabolism , Membrane Glycoproteins/metabolism , Membrane Transport Proteins , Nerve Tissue Proteins , Animals , Binding Sites , Binding, Competitive , Cocaine/metabolism , Dopamine Plasma Membrane Transport Proteins , Male , Molecular Structure , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Rhodium , Serotonin Plasma Membrane Transport Proteins , Structure-Activity Relationship , TritiumABSTRACT
In vitro studies have demonstrated that a novel tropane analog, PTT, in which both of the esters of cocaine have been removed is 20 times more potent than cocaine and more selective than cocaine in binding to dopamine transporters. The present studies compared the ability of PTT and cocaine to stimulate locomotor activity in rats. The intraperitoneal administration of PTT and cocaine to male Fisher-344 rats produced dose-dependent increases in spontaneous locomotor activity and stereotypic behaviors. PTT was 10-20 times more potent than cocaine in this behavioral assay, closely paralleling its potency relative to cocaine in dopamine transporter binding and uptake assays in vitro. PTT, however, elicited a qualitatively different profile of stereotypic behaviors, and PTT had a longer duration of action than cocaine. These results show how changes in kinetics and selectivity of tropanes can affect stimulant-elicited behaviors.
Subject(s)
Cocaine/pharmacology , Motor Activity/drug effects , Tropanes/pharmacology , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Male , Molecular Structure , Rats , Rats, Inbred F344 , Stereotyped Behavior/drug effects , Time FactorsABSTRACT
A novel scheme utilizing vinylcarbenoid precursors has been developed for the synthesis of novel tropane analogs of cocaine. Using this method, 15 analogs were prepared and tested for activity in binding to dopamine transporters in rat striatal membranes using [125I]RTI-55. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring (as in WIN 35,428), and methyl or ethyl ketone moieties were present at the 2 position instead of the typical ester group. The most potent analog was a 2-naphthyl derivative (IC50 value of 0.2 nM, vs. 170 nM for cocaine), while replacement of the aryl with either ethyl or cyclohexyl drastically reduced potency (to > 50 microM and 5 microM, respectively).