Synthesis and pharmacological characterization of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines as dopamine receptor ligands

A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1 dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine]. The affinity and selectivity of these isoquinolines for D1 receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to complete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2 receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1 sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl greater than 1-benzyl greater than 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 microM. D2 competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl greater than SCH23390 greater than 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.     

Synthesis of substituted 1-benzyl-1,2,3,4-tetrahydroisoquinolines]

Several derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline have been synthesized in order to evaluate their potential cardiovascular activities. These compounds, which can be related to Trimethoquinol and tetrahydropapaverin, showed no interesting activities in preliminary pharmacological screening.     

Evaluation of isomeric 4-(chlorohydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines as dopamine D-1 antagonists

The isomeric 4-(3-chloro-4-hydroxyphenyl)- and 4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines, the N-methyl derivative of the 4-(4-chloro-3-hydroxyphenyl) isomer, and 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline were synthesized and evaluated for dopamine D-1 antagonist activity. The 4-(3-chloro-4-hydroxyphenyl) and the 4-(3-hydroxyphenyl) isomer possessed similar potencies as D-1 antagonists. Introduction of the N-methyl group enhanced potency about twofold. The "pharmacophore" for selective dopamine D-1 antagonist activity appears to be a tertiary 2-(3-hydroxyphenyl)-2-phenethylamine.     

1-苄基-2-(4′-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物的合成及其抗心律失常活性(英文)

目的寻找具有Ⅲ/Ⅱ复合作用的新型抗心律失常药物。方法拼合1-苄基-1,2,3,4-四氢异喹啉与具有Ⅲ/Ⅱ复合作用的sotalol结构片段,设计合成1-苄基-2-(4′-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物,通过离体豚鼠心肌标本不应期测定法对所合成的目标化合物进行筛选。结果合成了18个未见文献报道的新化合物(1a-1r)。体外结果表明化合物1d、1e、1i、1j具有较好的延长动作电位时程的作用。结论化合物1d、1e、1i、1j表现出Ⅲ类抗心律失常药物延长动作电位时程的特征,有关Ⅲ/Ⅱ复合作用的药理实验有待进行。     

Synthesis, evaluation, and comparative molecular field analysis of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for histamine H(1) receptors.

A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to modulate tyrosine hydroxylase activity and dopamine synthesis in rodent forebrain through interaction with a binding site labeled by [(3)H]-(-)-(1R,3S)-trans-H(2)-PAT. Recently, we have discovered that PATs also bind with high affinity to the [(3)H]mepyramine-labeled H(1) receptor in rat and guinea pig brain. Here, we report the synthesis and biological evaluation of additional PAT analogues in order to identify differences in binding at these two sites. Further molecular modifications involve the pendant phenyl ring as well as quaternary amine compounds. Comparison of about 38 PAT analogues, 10 structurally diverse H(1) ligands, and several other CNS-active compounds revealed no significant differences in affinity at [(3)H]-(-)-trans-H(2)-PAT sites versus [(3)H]mepyramine-labeled H(1) receptors. These results, together with previous autoradiographic brain receptor-mapping studies that indicate similar distribution of [(3)H]-(-)-trans-H(2)-PAT sites and [(3)H]mepyramine-labeled H(1) receptors, suggest that both radioligands label the same histamine H(1) receptors in rodent brain. We also report a revision of our previous comparative molecular field analysis (CoMFA) study of the PAT ligands that yields a highly predictive model for 66 compounds with a cross-validated R(2) (q(2)) value of 0.67. This model will be useful for the prediction of high-affinity ligands at radiolabeled H(1) receptors in mammalian brain.     

Substituted phenoxyalkylpiperazines as dopamine D3 receptor ligands

A novel series of potential antipsychotic agents were prepared by combination of condensed heterocycles containing bridgehead nitrogen with (2-methoxyphenyl)piperazine using phenoxyalkyl spacer of variable length. The affinity of the compounds was determined at rat cloned D3 and rat D2, 5-HT1A receptors by an vitro receptor binding assay. The D3 selectivity of the compounds was calculated from the Ki values.     

1-苄基-2-(4''''-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物的合成及其抗心律失常活性

目的寻找具有Ⅲ／Ⅱ复合作用的新型抗心律失常药物。方法拼合1-苄基-1，2，3，4-四氢异喹啉与具有Ⅲ／Ⅱ复合作用的sotalol结构片段，设计合成1-苄基-2-（4’-甲磺酰基-1-羟基-苯乙基）-1，2，3，4-四氢异喹啉类化合物，通过离体豚鼠心肌标本不应期测定法对所合成的目标化合物进行筛选。结果合成了18个未见文献报道的新化合物（1a～1r）。体外结果表明化合物1d、1e、1i、1j具有较好的延长动作电位时程的作用。结论化合物1d、1e、1i、1j表现出Ⅲ类抗心律失常药物延长动作电位时程的特征，有关Ⅲ／Ⅱ复合作用的药理实验有待进行。     

Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands

A series of naphthamides were synthesized, and the affinities of these compounds were determined for dopamine D2 and D3 receptors using radioligand binding techniques. The naphthamide compounds that were prepared include N-(1-alkylpiperidin-4-yl)-4-bromo-1-methoxy-2-naphthamides (1-6), (S)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (7-12), (R)-N-(1-alkylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamides (13-18), (S)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (19-25), (R)-N-(1-alkyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamides (26-31), and N-(9-alkyl-9-azabicyclo[3.3.1]nonan-3beta-yl)-4-bromo-1-methoxy-2-naphthamides (32, 33). The results of in vitro radioligand binding studies indicated that the majority of the naphthamide analogues bound with high affinity at both the D2 and D3 dopamine receptor subtypes and most of the compounds demonstrated some selectivity for the dopamine D3 dopamine receptor subtype. These results demonstrated that both the structure of the central amine moiety (piperidine, pyrrolidine, and 9-azabicyclo[3.3.1]nonane) ring and the N-(alkyl) substitution on the amine significantly effects the binding affinity at D2 and D3 dopamine receptors. The bulkiness of the N-(1-alkyl) substituent was found to (a) have no effect on pharmacologic selectivity, (b) increase the affinity at D3 receptors, or (c) decrease the affinity at D2 receptors. The most potent analogue in this series was (S)-N-(1-cycloheptylpyrrolidin-3-yl)-4-bromo-1-methoxy-2-naphthamide (10), which had equilibrium dissociation (K(i)) values of 1.8 and 0.2 nM for D2 and D3 receptors, respectively. The most selective analogue was (R)-N-(1-cycloheptyl-2-pyrrolidinylmethyl)-4-bromo-1-methoxy-2-naphthamide (30), which had K(i) values of 62.8 and 2.4 nM for D2 and D3 receptors, respectively. Radioligand binding results for sigma receptors indicated that the structure of the amine moiety and the N-(1-alkyl) substitutions also significantly influence the affinity and selectivity of these compounds at the sigma1 and sigma2 sigma receptor subtypes. The two naphthamides containing a 9-azabicyclo[3.3.1]nonan-3beta-yl central ring were found to be selective for sigma2 receptors.     

Voltage-dependent block of N-methyl-D-aspartate receptors by dopamine D1 receptor ligands

Accumulating evidence indicates that dopamine and D1 receptor ligands modulate N-methyl D-aspartate (NMDA) receptors through a variety of D1 receptor-dependent mechanisms. In this study, we reveal a distinct D1 receptor-independent mechanism by which NMDA receptors are modulated. Using the human embryonic kidney (HEK) cell recombinant system and dissociated neurons, we have discovered that dopamine and several D1 ligands act as voltage-dependent, open-channel blockers for NMDA receptors, regardless of whether they are agonists or antagonists for D1 receptors. Analysis of structural and functional relationships of D1 ligands revealed the elements that are critical for their binding to NMDA receptors. Furthermore, using D1 receptor knockout mice, we verified that this channel-blocking effect was independent of D1 receptors. Finally, we demonstrated that D1 ligands functionally interact with Mg(2+) block through multiple sites, implying a possible role of the direct channel block under physiological conditions. Our results suggest that the direct inhibition of NMDA receptors by dopamine D1 receptor ligands is due to the channel pore block rather than receptor-receptor interactions.     

Dopamine D1 receptor and dopamine D2 receptor binding activity changes during chronic administration of nicotine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice

The effect of nicotine on MPTP-induced changes in striatal dopamine receptors binding activity was investigated. Dopamine D1 and D2 receptors were labeled with [3H]SCH-23390 and [3H]spiperone respectively in BALB/cBy mice. With administration of only MPTP, which caused more than an 80% decrease in striatal dopamine level, binding of 0.15 nM [3H]spiperone was increased by 37%; whereas 0.3 nM [3H]SCH-23390 binding was unchanged. With chronic nicotine treatment (0.4 mg/kg twice daily for 7-9 days), [3H]SCH-23390 binding activity was increased by 27% and [3H]spiperone binding activity was unchanged. When nicotine was administered after MPTP, their separate effects could be seen in that both the D1 and D2 dopamine receptor ligand binding activities were increased and that nicotine elevated the ratio of D1/D2 receptor binding activities in MPTP-treated mice.     

Synthesis of benzopyrano[3,4-c]pyridin-5-ones as dopamine D4 receptor ligands

The dopamine D4 receptor is highly expressed in prefrontal cortex, hippocampus, amygdala, hypothalamus and is hypothesized to relate with the pathophysiology and pharmacotherapy of schizophrenia while its level in brain regions is much lower. To date, no specific ligand is available for the study of D4 receptor in vivo. In this study, we report the synthesis and in vitro receptor binding assay of three benzopyrano[3,4-c]pyridin-5-ones as potential dopamine D4 receptor ligands. These new compounds have higher affinity and selectivity toward dopamine D4 receptor and their K(i) values for D4 receptor are in the nanomolar (nM) range.     

Dopamine receptor ligands. Part VII [1]: novel 3-substituted 5-phenyl-1, 2, 3, 4, 5, 6-hexahydro-azepino-[4, 5-b]indoles as ligands for the dopamine receptors

A number of 5‐phenyl‐1, 2, 3, 4, 5, 6‐hexahydro‐azepino‐[4, 5‐b]indoles 3 were synthesized with different substituents at the azepine‐N position (methyl‐, allyl‐, 2‐phenyl‐ethyl‐, cyclopropylmethyl‐ and unsubstituted). Furthermore, the indole‐N‐methylated compound was generated and by using norephedrines and norpseudoephedrines as a chiral pool, 4‐methyl‐5‐phenyl‐1, 2, 3, 4, 5, 6‐hexahydro‐azepino‐[4, 5‐b]indoles were prepared which contained racemisation at the reacting C‐atom. These compounds, as well as the ring‐open amino‐alcohols, were screened for their affinity to the hD₁‐, hD₅‐, hD_2L‐, and hD₄‐receptors (ç please check sentence). They had micromolar affinities for the receptors and showed the highest affinity to the D₁‐subtype family. The cyclic compounds possessed the highest affinity, with the cyclopropylmethyl‐( 3c ) and methyl‐substituents ( 3e ) being the most active of the tested compounds. Based on an intracellular cAMP‐assay, the unsubstituted compound (at the azepine‐N position) turned out to be an agonist for the D₁‐and D₅‐subtype family, whereas the substituted compounds showed (partial) agonistic, or even inverse agonistic activity.     

A theoretical study to investigate D2DAR/D4DAR selectivity: receptor modeling and molecular docking of dopaminergic ligands

Molecular modeling methods have been applied to construct three-dimensional models for dopaminergic ligand complexes with D2 and D4 receptor subtypes (D2DAR and D4DAR), using the bovine rhodopsin crystal structure as a template for the modeling study. Different dopaminergic ligands, in particular the N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines, were docked into the D2DAR and the D4DAR, to evaluate the agreement between theoretical and experimental results as regards their D2/D4 selectivity. The different position of an aromatic region in the two receptors might explain the structural basis of this biological property.     

Synthesis, biological activity, and molecular modeling of ribose-modified deoxyadenosine bisphosphate analogues as P2Y(1) receptor ligands

The structure-activity relationships of adenosine-3', 5'-bisphosphates as P2Y(1) receptor antagonists have been explored, revealing the potency-enhancing effects of the N(6)-methyl group and the ability to substitute the ribose moiety (Nandanan et al. J. Med. Chem. 1999, 42, 1625-1638). We have introduced constrained carbocyclic rings (to explore the role of sugar puckering), non-glycosyl bonds to the adenine moiety, and a phosphate group shift. The biological activity of each analogue at P2Y(1) receptors was characterized by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit its stimulation elicited by 30 nM 2-methylthioadenosine-5'-diphosphate (antagonist effect). Addition of the N(6)-methyl group in several cases converted pure agonists to antagonists. A carbocyclic N(6)-methyl-2'-deoxyadenosine bisphosphate analogue was a pure P2Y(1) receptor antagonist and equipotent to the ribose analogue (MRS 2179). In the series of ring-constrained methanocarba derivatives where a fused cyclopropane moiety constrained the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle, the 6-NH(2) (N)-analogue was a pure agonist of EC(50) 155 nM and 86-fold more potent than the corresponding (S)-isomer. The 2-chloro-N(6)-methyl-(N)-methanocarba analogue was an antagonist of IC(50) 51.6 nM. Thus, the ribose ring (N)-conformation appeared to be favored in recognition at P2Y(1) receptors. A cyclobutyl analogue was an antagonist with IC(50) of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives displayed micromolar potency as agonists (6-NH(2)) or antagonists (N(6)-methyl). A molecular model of the energy-minimized structures of the potent antagonists suggested that the two phosphate groups may occupy common regions. The (N)- and (S)-methanocarba agonist analogues were docked into the putative binding site of the previously reported P2Y(1) receptor model.     

New series of morpholine and 1,4-oxazepane derivatives as dopamine D4 receptor ligands: synthesis and 3D-QSAR model

Since the identification of the dopamine D(4) receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D(4) ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D(4) receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.