Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate.
A series of threo-1-aza-3 or 4-substituted-5-phenyl[4.4.0]decanes (quinolizidines), which were envisioned as restricted rotational analogues (RRAs) of methylphenidate (MP), was synthesized and tested for inhibitory potency against [(3)H]WIN35,428, [3H]citalopram, and [3H]nisoxetine binding to the dopamine, serotonin, and norepinephrine transporters, respectively. Two different synthetic schemes were used; a Wittig reaction or acylation (followed by an intramolecular condensation) was a key feature of each scheme. The unsubstituted RRA, threo(trans)-1-aza-5-phenyl[4.4.0]decane (12a), was equipotent to unconstrained threo-MP against [(3)H]WIN35,428 binding. The extra ring in these RRAs (which reduces the conformational freedom) and the orientation and polarity of substituents at the 4-position on this extra ring are of critical importance to the biological activity. Generally, the RRAs paralleled the corresponding unconstrained MP derivatives in binding affinity to the three transporters. The results suggest that the conformation of MP in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N-H may be the bioactive form of the molecule.
Kim
Deog-Il
DI
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
Deutsch
Howard M
HM
Ye
Xiaocong
X
Schweri
Margaret M
MM
D000818:Animals; D001921:Brain / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008774:Methylphenidate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D011807:Quinolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C520850:1-aza-4-ethyl-5-(3,4-dichlorophenyl)bicyclo(4.4.0)decane; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050483:Dopamine Plasma Membrane Transport Proteins; D011807:Quinolizines; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D015283:Citalopram; C011386:nisoxetine; D008774:Methylphenidate; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine