Synthesis of 3β-Aryl-8-azabicyclo[3.2.1]octanes with High Binding Affinities and Selectivities for the Serotonin Transporter Site

• Published in: Journal of medicinal chemistry Vol. 39; no. 13; pp. 2554 - 2558
• Main Authors: Davies, Huw M. L, Kuhn, Lisa A, Thornley, Craig, Matasi, Julius J, Sexton, Tammy, Childers, Steven R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.06.1996; Amer Chemical Soc
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Carrier Proteins - metabolism; Chemistry, Medicinal; Cocaine - analogs & derivatives; Cocaine - metabolism; Corpus Striatum - metabolism; Dopamine; Dopamine Plasma Membrane Transport Proteins; Fluoxetine - analogs & derivatives; Fluoxetine - metabolism; Frontal Lobe - metabolism; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Membrane Glycoproteins - metabolism; Membrane Transport Proteins; Molecular Structure; Nerve Tissue Proteins; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine - metabolism; Norepinephrine Plasma Membrane Transport Proteins; Paroxetine - metabolism; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins; Serotonin Uptake Inhibitors - metabolism; Serotoninergic system; Structure-Activity Relationship; Symporters; Tropanes - chemical synthesis; Tropanes - chemistry; Tropanes - metabolism; Tropanes - pharmacology; COCAINE; INHIBITION; PROVIDES; ANALOGS; DOPAMINE TRANSPORTER; ESTERS; Rat; Serotonin; Nitrogen heterocycle; Rodentia; Central nervous system; Benzene derivatives; Selectivity; In vitro; Naphthalene derivatives; Vertebrata; Biological fixation; Mammalia; Aminoketone; Structure activity relation; Membrane transport; Animal; Bicyclic compound; Affinity; Cocaine; Drug of abuse; Chemical synthesis; Carrier protein; Brain (vertebrata); Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9600508

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3β-[4-(1-methylethenyl)phenyl]-2β-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a K i of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.