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Nitrogen‐based drugs are not essential for blockade of monoamine transporters
Author(s) -
Madras Bertha K.,
Niznik Hyman B.,
Liang Anna Y.,
Blundell Paul,
Gonzalez Mario D.,
Meltzer Peter C.
Publication year - 1996
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199612)24:4<340::aid-syn4>3.0.co;2-d
Subject(s) - monoamine neurotransmitter , pharmacology , dopamine transporter , dopamine , chemistry , transporter , serotonin , biogenic amine , ic50 , organic cation transport proteins , biochemistry , receptor , biology , neuroscience , in vitro , gene
In brain, monoamine transporters are principal targets of widely used therapeutic drugs including antidepressants, methylphenidate (Ritalin), and the addictive drug cocaine. Without exception, these transport blocking agents contain an amine nitrogen. A prevalent view and untested promise is that an amino nitrogen is needed to bind to the same counterion on the transporter as does the amino nitrogen of the monoamine neurotransmitter. We report that several compounds without nitrogen (8‐oxa‐bicyclo‐3‐aryl‐[3.2.1] octanes, or aryloxatropanes) are active at monoamine transporters. One of these, tropoxane (O‐914), bound with high affinity to the dopamine (IC ??? : 3.35 ± 0.39 nM), serotonin (IC ??? 6.52 ± 2.05 nM), and norepinophrine (IC ??? : 20.0 ± 0.3 nM) transporters in monkey brain, the human striatal dopamine transporter (IC ??? : 5.01 ± 1.74 nM), and blocked dopamine transport (IC ??? : 7.2 ± 3.0 nM) in COS‐7 cells transfected with the human dopamine transporter. These unique compounds require a revision of current concepts of the drug binding domains on monoamine transporters, open avenues for discovery of a new generation of drugs and raise the issue of whether mammalian transporters and receptors may respond to, as yet, undiscovered non‐amine bearing neurotransmitters or drugs. © 1996 Wiley‐Liss, Inc.