2,5-Disubstituted tetrahydrofurans as selective serotonin re-uptake inhibitors.
Enhancement of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission is a viable means of treating depression. On the basis of this observation, agents that inhibit re-uptake of 5-HT were prepared based on (-)-cocaine and aryltropanes as lead compounds because they are reasonably potent 5-HT re-uptake inhibitors. Molecular dissection of an aryltropane provided a series of 5- and 6-membered ring compounds. From among this library of compounds a series of disubstituted tetrahydrofurans bearing 2-alkyl aryl and 5-alkyl amino groups were identified as having highly potent and selective 5-HT re-uptake inhibition. The compounds were evaluated for their ability to compete with radiolabeled RTI-55 binding and to inhibit re-uptake of neurotransmitters at the human dopamine, serotonin and norepinephrine transporters. Based on potency (e.g., K(i)=800 pM) and significant functional selectivity (e.g., IC(50) ratios for human dopamine:serotonin or norepinephrine:serotonin, >or=1397) highly potent and selective serotonin re-uptake inhibitors were identified. Optimal features playing a dominant role in binding affinity and re-uptake inhibition included lipophilic substitution on the aromatic moiety, trans relative stereochemistry of the 2,5-disubstituted tetrahydrofuran ring, and a total of four or five methylene groups between the alkyl amine and the alkyl aryl moiety and the tetrahydrofuran group. A number of the most potent serotonin re-uptake inhibitors were tested in Balb/c mice in the forced-swim test (FST), a behavioral test used to measure the effects of antidepressant agents. Acute administration of 32c (10mg/kg), or 32d (10mg/kg) ip tended to decrease the duration of mouse immobility in the FST although the effect was not statistically significant.
Voelker
Troy
T
Human BioMolecular Research Institute, San Diego, CA 92121, USA.
Xia
Haiji
H
Fandrick
Keith
K
Johnson
Robert
R
Janowsky
Aaron
A
Cashman
John R
JR
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003042:Cocaine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013550:Swimming
D000928:Antidepressive Agents; D003042:Cocaine; D004298:Dopamine; D005663:Furans; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane