March 24, 2008
New SSRI compounds may improve upon Prozac and Paxil. D. Zhou and G. P. Stack disclose novel compounds that inhibit serotonin reuptake in the mammalian brain and are antagonists of the 5HT1A receptors. These compounds may lead to developing drugs to treat depression and related diseases and conditions, including attention deficit disorder, obsessive–compulsive behavior, anxiety, obesity, and drug and alcohol addiction.
Major depression is a serious health problem that affects >5% of the population. Selective serotonin reuptake inhibitors (SSRIs), which increase the effective concentration of serotonin in the brain by inhibiting its reuptake in the neuronal synapse, are effective treatments for this problem in many, but not all patients. These drugs include N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]-propan-1-amine (fluoxetine, 1), trade name Prozac; and (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperdine (paroxetine, 2), trade name Paxil.
Some researchers suggest that a single dose of an SSRI may increase the level of serotonin in the serotonergic cell bodies available to bind to the somatodendritic autoreceptors (5HT1A receptors), causing a decrease in the amount of serotonin released in some areas of the forebrain. This negative feedback response reduces the effective level of serotonin in the neuronal synapse that can be achieved by administering most SSRIs.
The inventors describe compounds that function as SSRIs and as antagonists of the 5HT1A receptor. These compounds inhibit the reuptake of serotonin, and they prevent serotonin from binding to the receptor responsible for signaling the neuron to reduce production of serotonin. These compounds promise to be more effective SSRIs than the drugs now used to treat depression and other disorders related to serotonin levels in the brain.
The compounds include: 2-[3-(5-fluoro-1H-indol-3-ylmethyl)azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; 2-[3-(1H-indol-3-ylmethyl)azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; and 2-[3-(5-fluoro-1-methyl-1H-indol-3-ylmethyl)azetidin-1-ylmethyl]-8-methyl-2,3-dihydro-1[1,4]dioxino[2,3-f]quinoline.
Future work in this area will likely include testing these compounds in animal models to determine their toxicity and efficacy as treatments for disorders that relate to serotonin levels in the brain. Additional work will likely include the synthesizing and testing of derivatives of these compounds to attempt to identify useful compounds for treating depression and other problems with similar chemical etiologies. (Wyeth [Madison, NJ]. U.S. Patent 7,335,666, Feb 26, 2008; John Emanuele)
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