Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.
BACKGROUND
Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine.


OBJECTIVE
A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions.


METHODS
Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques.


RESULTS
All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs.


CONCLUSIONS
The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.
Katz
J L
JL
Psychobiology Section, Medications Discovery Research Branch, NIDA Intramural Research Program, National Institutes of Health, P.O. Box 5180, Baltimore, MD 21224, USA.
Agoston
G E
GE
Alling
K L
KL
Kline
R H
RH
Forster
M J
MJ
Woolverton
W L
WL
Kopajtic
T A
TA
Newman
A H
AH
D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001590:Benztropine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters
C105321:4'-chloro-3-(diphenylmethoxy)tropane; D000978:Antiparkinson Agents; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D001590:Benztropine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine