Abstract
A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at μ-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (Ki = 0.0072 μM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and μ-opioid receptors (μ/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K i = 0.125 μM) and was the most selective ligand for the DAT over μ-opioid receptors (μ/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the μ-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
| Original language | English |
|---|---|
| Pages (from-to) | 1336-1343 |
| Number of pages | 8 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 48 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 10 2005 |
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ASJC Scopus subject areas
- Organic Chemistry
Cite this
Synthesis and biological evaluation of meperidine analogues at monoamine transporters. / Lomenzo, Stacey A.; Rhoden, Jill B.; Izenwasser, Sari E; Wade, Dean; Kopajtic, Theresa; Katz, Jonathan L.; Trudell, Mark L.
In: Journal of Medicinal Chemistry, Vol. 48, No. 5, 10.03.2005, p. 1336-1343.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and biological evaluation of meperidine analogues at monoamine transporters
AU - Lomenzo, Stacey A.
AU - Rhoden, Jill B.
AU - Izenwasser, Sari E
AU - Wade, Dean
AU - Kopajtic, Theresa
AU - Katz, Jonathan L.
AU - Trudell, Mark L.
PY - 2005/3/10
Y1 - 2005/3/10
N2 - A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at μ-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (Ki = 0.0072 μM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and μ-opioid receptors (μ/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K i = 0.125 μM) and was the most selective ligand for the DAT over μ-opioid receptors (μ/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the μ-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
AB - A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at μ-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (Ki = 0.0072 μM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and μ-opioid receptors (μ/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K i = 0.125 μM) and was the most selective ligand for the DAT over μ-opioid receptors (μ/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the μ-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
UR - http://www.scopus.com/inward/record.url?scp=14944369844&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=14944369844&partnerID=8YFLogxK
U2 - 10.1021/jm0401614
DO - 10.1021/jm0401614
M3 - Article
C2 - 15743177
AN - SCOPUS:14944369844
VL - 48
SP - 1336
EP - 1343
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -