Abstract
A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aporphines / chemical synthesis*
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Aporphines / chemistry
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Aporphines / pharmacology*
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CHO Cells
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Cells, Cultured
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Cricetinae
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Cricetulus
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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Kidney / cytology
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Kidney / drug effects
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Magnetic Resonance Spectroscopy
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Male
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Maze Learning / drug effects
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Neurons / cytology
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Neurons / drug effects
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Radioligand Assay
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Rats
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Rats, Sprague-Dawley
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / metabolism
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Serotonin 5-HT1 Receptor Agonists*
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Serotonin Receptor Agonists / chemical synthesis*
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Serotonin Receptor Agonists / chemistry
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Serotonin Receptor Agonists / pharmacology*
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Structure-Activity Relationship
Substances
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11-allyloxy-N-methylaporphine
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11-propargyloxy-N-methylaporphine
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Aporphines
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N-methyl-2'-methyl-2',3'-dihydrofuro(m)aporphine
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Serotonin 5-HT1 Receptor Agonists
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Serotonin Receptor Agonists
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Guanosine 5'-O-(3-Thiotriphosphate)