Novel C-1 substituted cocaine analogs unlike cocaine or benztropine.
Despite a wealth of information on cocaine-like compounds, there is no information on cocaine analogs with substitutions at C-1. Here, we report on (R)-(-)-cocaine analogs with various C-1 substituents: methyl (2), ethyl (3), n-propyl (4), n-pentyl (5), and phenyl (6). Analog 2 was equipotent to cocaine as an inhibitor of the dopamine transporter (DAT), whereas 3 and 6 were 3- and 10-fold more potent, respectively. None of the analogs, however, stimulated mouse locomotor activity, in contrast to cocaine. Pharmacokinetic assays showed compound 2 occupied mouse brain rapidly, as cocaine itself; moreover, 2 and 6 were behaviorally active in mice in the forced-swim test model of depression and the conditioned place preference test. Analog 2 was a weaker inhibitor of voltage-dependent Na+ channels than cocaine, although 6 was more potent than cocaine, highlighting the need to assay future C-1 analogs for this activity. Receptorome screening indicated few significant binding targets other than the monoamine transporters. Benztropine-like "atypical" DAT inhibitors are known to display reduced cocaine-like locomotor stimulation, presumably by their propensity to interact with an inward-facing transporter conformation. However, 2 and 6, like cocaine, but unlike benztropine, exhibited preferential interaction with an outward-facing conformation upon docking in our DAT homology model. In summary, C-1 cocaine analogs are not cocaine-like in that they are not stimulatory in vivo. However, they are not benztropine-like in binding mechanism and seem to interact with the DAT similarly to cocaine. The present data warrant further consideration of these novel cocaine analogs for antidepressant or cocaine substitution potential.
Department of Psychiatry, New York University School of Medicine, 450 E 29th Street, Alexandria Building Room 803, New York, NY 10016, USA. maarten.reith@nyumc.org
Maarten E A
ME
Reith
Solav
S
Ali
Audrey
A
Hashim
Imran S
IS
Sheikh
Naresh
N
Theddu
Narendra V
NV
Gaddiraju
Suneet
S
Mehrotra
Kyle C
KC
Schmitt
Thomas F
TF
Murray
Henry
H
Sershen
Ellen M
EM
Unterwald
Franklin A
FA
Davis
D000818:Animals; D001590:Benztropine / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005260:Female; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D019579:Neocortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D011247:Pregnancy; D011485:Protein Binding; D011487:Protein Conformation; D011869:Radioligand Assay; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship; D013550:Swimming / Q000523:psychology; D014701:Veratridine / Q000494:pharmacology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007202:Indicators and Reagents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D015222:Sodium Channels; D001590:Benztropine; D014701:Veratridine; D012964:Sodium; D003042:Cocaine