Abstract:Prior work in these laboratories identified (+/-)-5-hydroxy-6-methyl-2- (di-n-propylamino)tetralin as a dopaminergic agonist prodrug. The ortho methyl hydroxy aromatic substitution pattern in this molecule has now been incorporated into the aporphine ring system to give a congener of the dopaminergic agonist apomorphine in which the position 10 OH group has been replaced by methyl. Preparation of the target compound involved acid-catalyzed rearrangement of the 3-(1-phenyltetrazolyl) ether of morphine and subse… Show more
“…( − )-( R )-Aporphine (7) 5c. A mixture of 6 (223 mg, 0.58 mmol), (diphenylphosphino)propane (dppp; 37 mg, 0.089 mmol), (PPh 3 ) 2 PdCl 2 (25 mg, 0.035 mmol), Bu 3 N (0.55 mL, 2.31 mmol), and formic acid (66 μL, 1.8 mmol) in dry DMF (5 mL) was stirred at 80 °C for 15 h. The volatiles were evaporated in vacuo , and the residue was partitioned between CH 2 Cl 2 and 10% aqueous NaHCO 3 .…”
Section: Methodsmentioning
confidence: 99%
“…Compound (±)- 4 , 1e, the racemic C11-methoxy analogue of 3 , was almost devoid of DA receptor agonist properties . In addition, the C10-methyl analogue of 3 , compound 5 (HYMAP), was recently shown to be a potent and selective 5-HT 1A receptor agonist. , …”
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
“…( − )-( R )-Aporphine (7) 5c. A mixture of 6 (223 mg, 0.58 mmol), (diphenylphosphino)propane (dppp; 37 mg, 0.089 mmol), (PPh 3 ) 2 PdCl 2 (25 mg, 0.035 mmol), Bu 3 N (0.55 mL, 2.31 mmol), and formic acid (66 μL, 1.8 mmol) in dry DMF (5 mL) was stirred at 80 °C for 15 h. The volatiles were evaporated in vacuo , and the residue was partitioned between CH 2 Cl 2 and 10% aqueous NaHCO 3 .…”
Section: Methodsmentioning
confidence: 99%
“…Compound (±)- 4 , 1e, the racemic C11-methoxy analogue of 3 , was almost devoid of DA receptor agonist properties . In addition, the C10-methyl analogue of 3 , compound 5 (HYMAP), was recently shown to be a potent and selective 5-HT 1A receptor agonist. , …”
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
“…In fact, the indoline 48 displayed an astounding 5-HT 1A selectivity for a compound of this class. Cannon et al [70,71] published the 10-methyl substituted derivative of 49, (R)-(-)-10-methyl-11-hydroxyaporphine, (50 MHA) in an effort to further study structure-activity relationships (SAR) of (R)-aporphines at DA receptors (Fig. 12).…”
Serotonin is a neuromediator, well-know for its implication in mood regulation, anxiety, depression and, insomnia as well as in normal human function such as sleep, sexual activity and appetite. In this way, serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists and pharmaceutical companies. Among 5-HTRs, the 5-HT1A subtype is the best studied, and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT1A receptor sites such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines and aryloxyalkyl-amines. In this review, we report an overview of the 5-HT1A receptor ligands, belonging to different chemical classes.
“…Compound 2, on the other hand, was shown to be a partial agonist. It inhibited FSC to about 60% of t h e maximal effect produced by 5-HT.The in vivo effects of 2 and 3 on rat hippocampal output of 5-HT,5-hydroxyindoleacetic acid (5-HIAA), and dihydroxyphenylacetic acid (DOPAC) were studied using in vivo microdialysis. The dialysate levels of 5-HT, 5-HIAA, and DOPAC were taken as indices of 5-HT release and metabolisdturnover and catecholamine [mainly norepinephrine (NA)] metabolisdturnover, r e s p e~t i v e l y .~~ Compound 3 induced a dose-and time-dependent suppresion of the rat ventral hippocampal 5-HT release…”
(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
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