ABSTRACT
The power of the Cloud has been harnessed for pharmaceutical compound production with remote servers based in Tokyo, Japan being left to autonomously find optimal synthesis conditions for three active pharmaceutical ingredients (APIs) in laboratories in Cambridge, UK. A researcher located in Los Angeles, USA controlled the entire process via an internet connection. The constituent synthetic steps for Tramadol, Lidocaine, and Bupropion were thus optimized with minimal intervention from operators within hours, yielding conditions satisfying customizable evaluation functions for all examples.
Subject(s)
Analgesics, Opioid/chemical synthesis , Anesthetics, Local/chemical synthesis , Antidepressive Agents, Second-Generation/chemical synthesis , Bupropion/chemical synthesis , Chemistry Techniques, Synthetic/methods , Lidocaine/chemical synthesis , Tramadol/chemical synthesis , Chemistry Techniques, Synthetic/economics , Chemistry Techniques, Synthetic/instrumentation , Cloud Computing/economics , Drug Industry/economics , Drug Industry/instrumentation , Drug Industry/methods , Equipment Design , Japan , United Kingdom , United StatesABSTRACT
This paper describes the synthesis of deuterium-labeled hydroxybupropion. Mass spectrometry analysis of the compound revealed over 98% deuterium enrichment.
Subject(s)
Antidepressive Agents, Second-Generation/chemical synthesis , Bupropion/analogs & derivatives , Deuterium/chemistry , Bupropion/chemical synthesisABSTRACT
Towards addressing the knowledge gap of how bupropion interacts with the dopamine transporter (DAT) and nicotinic acetylcholine receptors (nAChRs), a ligand was synthesized in which the chlorine of bupropion was isosterically replaced with an iodine and a photoreactive azide was added to the 4'-position of the aromatic ring. Analog (±)-3 (SADU-3-72) demonstrated modest DAT and α4ß2 nAChR affinity. A radioiodinated version was shown to bind covalently to hDAT expressed in cultured cells and affinity-purified, lipid-reincorporated human α4ß2 neuronal nAChRs. Co-incubation of (±)-[(125)I]-3 with non-radioactive (±)-bupropion or (-)-cocaine blocked labeling of these proteins. Compound (±)-[(125)I]-3 represents the first successful example of a DAT and nAChR photoaffinity ligand based on the bupropion scaffold. Such ligands are expected to assist in mapping bupropion-binding pockets within plasma membrane monoamine transporters and ligand-gated nAChR ion channels.
Subject(s)
Azides/chemical synthesis , Azides/pharmacology , Bupropion/analogs & derivatives , Bupropion/pharmacology , Chemistry, Pharmaceutical/methods , Receptors, Nicotinic/metabolism , Azides/chemistry , Bupropion/chemical synthesis , Dopamine Plasma Membrane Transport Proteins/metabolism , Drug Design , Humans , Iodine/chemistry , Iodine Radioisotopes/chemistry , Kinetics , Ligands , Models, Chemical , Photochemistry/methodsABSTRACT
To create potentially superior aids to smoking cessation and/or antidepressants and to elucidate bupropion's possible mechanisms of action(s), 23 analogues based on its active hydroxymetabolite (2S,3S)-4a were synthesized and tested for their abilities to inhibit monoamine uptake and nAChR subtype activities in vitro and acute effects of nicotine in vivo. The 3',4'-dichlorophenyl [(+/-)-4n], naphthyl (4r), and 3-chlorophenyl or 3-propyl analogues 4s and 4t, respectively, had higher inhibitory potency and/or absolute selectivity than (2S,3S)-4a for inhibition of DA, NE, or 5HT uptake. The 3'-fluorophenyl, 3'-bromophenyl, and 4-biphenyl analogues 4c, 4d, and 4l, respectively, had higher potency for antagonism of alpha4beta2-nAChR than (2S,3S)-4a. Several analogues also had higher potency than (2S,3S)-4a as antagonists of nicotine-mediated antinociception in the tail-flick assay. The results suggest that compounds acting via some combination of DA, NE, or 5HT inhibition and/or antagonism of alpha4beta2-nAChR can potentially be new pharmacotherapeutics for treatment of nicotine dependence.
Subject(s)
Adrenergic Uptake Inhibitors/chemical synthesis , Bupropion/analogs & derivatives , Dopamine Uptake Inhibitors/chemical synthesis , Nicotinic Antagonists/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Analgesics/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Body Temperature/drug effects , Bupropion/chemical synthesis , Bupropion/chemistry , Bupropion/pharmacology , Cell Line , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Humans , Male , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/chemistry , Nicotinic Antagonists/pharmacology , Receptors, Nicotinic/physiology , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Smoking Cessation , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of bupropion (1a) analogues (1b-1ff) were synthesized, and their in vitro and in vivo pharmacological properties evaluated with the goal of developing a 1a analogue that had better properties for treating addictions. Their in vitro pharmacological properties were examined by [(3)H]dopamine ([(3)H]DA), [(3)H]serotonin ([(3)H]5HT), and [(3)H]norepinephrine ([(3)H]NE) uptake inhibition studies, and by binding studies at the dopamine, serotonin, and norepinephrine transporters using [(125)I]RTI-55 in cloned transporters. Several analogues showed increased [(3)H]DA uptake inhibition with reduced or little change in [(3)H]5HT and [(3)H]NE uptake inhibition relative to bupropion. Thirty-five analogues were evaluated in a 1 h locomotor activity observation test and 32 in an 8 h locomotor activity observation test and compared to the locomotor activity of cocaine. Twenty-four analogues were evaluated for generalization to cocaine drug discrimination after i.p. administration, and twelve analogues were tested in a time course cocaine discrimination study using oral administration. 2-(N-Cyclopropylamino)-3-chloropropiophenone (1x) had the most favorable in vitro efficacy and in vivo pharmacological profile for an indirect dopamine agonist pharmacotherapy for treating cocaine, methamphetamine, nicotine, and other drugs of abuse addiction.
Subject(s)
Bupropion/analogs & derivatives , Bupropion/chemical synthesis , Cocaine-Related Disorders/drug therapy , Cocaine/pharmacology , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Animals , Bupropion/pharmacology , Cell Line , Discrimination Learning/drug effects , Dopamine Plasma Membrane Transport Proteins/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Humans , Mice , Motor Activity/drug effects , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Radioligand Assay , Rats , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The synthesis of the enantiomers of bupropion, (rac)-2-tert-butylamino-3'-chloropropiophenone 1 (Wellbutrin) is described. The enantiomers were compared with the racemate in both the tetrabenazine-induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain.
