Synthesis and pharmacology of site specific cocaine abuse treatment agents: 8-substituted isotropane (3-azabicyclo[3.2.1]octane) dopamine uptake inhibitors.
A series of 8-substituted-3-azabicyclo[3.2.1]octanes (isotropanes) were synthesized and tested for inhibitor potency using [(3)H]WIN 35,428 binding at the dopamine (DA) transporter, [(3)H]citalopram binding at the serotonin (5-HT) transporter, and [(3)H]DA uptake assays. The synthesis started with a Mannich condensation of cyclopentanone, benzylamine, and fomaldehyde to afford N-benzyl-3-azabicyclo[3.2.1]octan-8-one (6). The 8-phenyl group was introduced by Grignard addition to ketone 6 or nucleophilic displacement via a triflate of the corresponding alcohol 7a. The 8beta-phenyl-8alpha-alcohols from Grignard addition generally have low affinity for the two transporters and do not effectively inhibit the uptake of [(3)H]DA. The 8beta-phenyl compound (14) without the hydroxyl group at C-8 was much more potent (22-fold) for [(3)H]WIN 35,428 binding inhibition than the corresponding 8beta-phenyl-8alpha-hydroxy compound (7a). The 8alpha-phenyl compound 8a was almost as potent as cocaine in binding to the DA transporter (IC(50) = 234 nM vs 159 nM for cocaine), whereas the C-8 epimer, compound 14, was somewhat less potent (IC(50) = 785 nM). The lower potency of 14 (beta-orientation of 8-phenyl group) as compared to 8a (alpha-orientation) was unexpected, based on modeling studies comparing the new compounds to WIN 35,065-2, an analogue of cocaine. The benzhydryl ethers at C-8 (17), analogous to the benztropines, had better selectivity than the corresponding phenyl compounds, 8a and 14, for the DA transporter as compared to the 5-HT transporter. The isotropane and benzisotropine analogues seem to bind in a manner that is more similar to that of the benztropine compounds 5 rather than those of cocaine and WIN 35,065-2.
Kim
Deog-Il
DI
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400, USA.
Schweri
Margaret M
MM
Deutsch
Howard M
HM
D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors; D008566:Membranes; D009419:Nerve Tissue Proteins; D009795:Octanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009795:Octanes; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D004298:Dopamine