trans-2,6-, 3,6- and 4,6-Diaza-5,6,6a,7,8,12b-hexahydrobenzo[C]phenanthrene-10,11-diols as dopamine agonists (original) (raw)
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Journal of Medicinal Chemistry, 1994
Racemic trans -10,ll -dihydroxy-5,6,6a, 7,8,12b-hexahydrobenzo[a]phenanthridine (2, dihydrexidine) was shown previously to be the first bioavailable full efficacy agonist at the D1 dopamine receptor. In addition to its full D1 agonist properties, 2 also is a good ligand for D2-like dopamine receptors. The profound anti-Parkinsonian actions of this compound make determination of its enantioselectivity at both D1 and D2 receptors of particular importance. To accomplish this, the enantiomers were resolved by preparation of diastereomeric (R)-O-methylmandelic acid amides of racemic trans-l0,ll-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[alphenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-iV-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and 0,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (GaR,12bS)-(+)-enantiomer 2 had about twice the affinity of the racemate and 25-fold greater affinity than the (-)-enantiomer at the D1 receptor labeled by [3HlSCH23390 (KO.@ of 5.6, 11.6, and 149 nM, respectively). Similarly, the (+)-enantiomer 2 had about twice the affinity of the racemate for human D1 receptors expressed in transfected Ltk-cells. Functionally, the (+)-enantiomer of 2 was a full agonist, with an EC5o of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 pM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K 0 . 5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 pM for the (-)-enantiomer. Together, these data demonstrate that both the D1 and D2 activities of dihydrexidine reside principally in the (6aR,12bS)-(+)-enantiomer. The results are discussed in the context of structure-activity relationships and conceptual models of the D1 receptor.
Cheminform, 2010
With a straightforward seven-step synthesis, racemic perhydro benzoxazin-6-on was synthesized in overall good yields via regioselective epoxid ring-opening to the corresponding -aminoalcohol. The oxazine derivative was the key intermediate for the preparation of heteroaromatic analogues of the dopamine D 3 -receptor preferring agonist PD 128,907. The morpholine moiety of PD 128,907 was incorporated in diazole and diazine compounds obtained by different ring closure reactions. The target compounds obtained were structurally related to non-ergot heteroaromatic dopamine agonists which display preferential activity at the D 3 receptor, e.g., quinpirole, quinerolane, or pramipexole. The five membered aminothiazole, aminoselenazole, and pyrazole derivatives showed at least one order of magnitude higher binding at the human D 3 receptor than that at the D 2L receptor. Although the novel compounds displayed K i values only in the micromolar concentration range, the most active ones showed full agonist activity in a functional assay on mitogenesis. © 1999 Éditions scientifiques et médicales Elsevier SAS dopamine / D 3 -receptor / D 2 -receptor / PD 128,907 / agonist / mitogenesis / pramipexole / quinpirole / quinerolane
Journal of medicinal chemistry, 1990
trans-10,11-Dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenan thridine (4a, dihydrexidine) has been found to be a highly potent and selective agonist of the dopamine D1 receptor in rat brain. Dihydrexidine had an EC50 of approximately 70 nM in activating dopamine-sensitive rat striatal adenylate cyclase and a maximal stimulation equal to or slightly greater than that produced by dopamine. Dihydrexidine had an IC50 of 12 nM in competing for [3H]SCH23390 (1a) binding sites in rat striatal homogenate, and of 120 nM versus [3H]spiperone. These data demonstrate that dihydroxidine has about ten-fold selectivity for D1/D2 receptors. More importantly, however, is the fact that dihydrexidine is a full agonist. Previously available agents, such as SKF38393 (1b), while being somewhat more selective for the D1 receptor, are only partial agonists. The isomeric cis-dihydroxybenzo[a]-phenanthridine neither stimulated cAMP synthesis nor inhibited the cAMP synthesis induced by dopamine. The cis isome...
Functionally Selective Dopamine D 2 /D 3 Receptor Agonists Comprising an Enyne Moiety
Journal of Medicinal Chemistry, 2013
Contents 1) 1 Hand 13 C-NMR Data of the Target Compounds……………………………. S2 2) HPLC Data of the Target Compounds…………………………………………. S8 3) Chiral Separation………………………………………………………………… S14 4) X-ray Crystal Structure Determination of 3,5-dinitrobenzamide (S)-7………. S15 5) Dose-Response Curves of the Target Compounds in the [ 35 S]GTPγS Assay… S26 6) Representative Dose-Response Curves of the Reference Compounds Ropinirole and Rotigotine in a [ 35 S]GTPγS Assay with D 2long Expressing Cells………………..… S29 7) Comparison of the Binding Affinities of Representative Compounds at the D 2long Receptor Stably Expressed in CHO Cells and Transiently Expressed in HEK 293 Cells as well as at Membranes from Porcine Striatum………………………………….. S30 8) Amino acid sequence alignment of DRD2, DRD3, 5HT1B and 5HT2B………. S31 S2 1) 1 Hand 13 C-NMR Data and HPLC Data of the Target Compounds (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}biphenyl-4-carboxamide ((R)-1) 1 H-NMR 1 H (600MHz, CD 3 OD) 13 C-NMR 13 C (360MHz, CD 3 OD) S3 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-2carboxamide ((R)-2a). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S4 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}pyrazolo[1,5-a]pyridine-3carboxamide ((R)-2b) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (600MHz, CDCl 3) S5 (R)-4-[3-(1-Butyl-1H-1,2,3-triazol-4-yl)propoxy]-N-{4-[(6-ethynylcyclohex-3enyl)propylamino]-butyl}-3-methoxybenzamide ((R)-2c) 1 H-NMR 1 H (360MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3) S6 (R)-N-{4-[(4-Ethynylcyclohex-3-enyl)propylamino]butyl}benzo[b]thiophene-2carboxamide ((R)-2d). 1 H-NMR 1 H (600MHz, CDCl 3) 13 C-NMR 13 C (360MHz, CDCl 3)
Dihydrexidine: a new potent peripheral dopamine D1 receptor agonist
European Journal of Pharmacology, 1993
Dihydrexidine (trans-10,11-dihydroxyhexahydrobenzo-[a]phenanthridine) was found to be a full dopamine D~ receptor agonist with a potency five times that of dopamine. Dihydrexidine showed no agonist activity at peripheral dopamine O 2 receptors, c~-or ~-adrenoceptors at the doses which produced near maximal stimulation of dopamine D 1 receptors. The chemical structure of dihydrexidine shows that addition of a phenyl ring to a benzo[f]quinoline moiety bestows potent D~ activity upon a structure which had no such activity previously. This observation introduces a new factor in structure-activity considerations for dopamine receptor ligands. Dihydrexidine; Dopamine receptor ligands; Dopamine receptors (peripheral) 10 min. The renal blood flow and carotid blood pressure were recorded at the end of each infusion period. The infusion rate was then increased.
Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands
European Journal of Pharmacology, 1993
We report that certain substituted hexahydrobenzo [a]phenanthridines are novel high affinity ligands selective for the dopamine D 3 receptor. These data demonstrate that substitutions on the heterocyclic nitrogen and the pendant phenyl ring of this nucleus cause a marked increase in both affinity and selectivity for dopamine D 3 vs. D 2 receptors. Thus, these compounds represent important new tools to study the pharmacology of dopamine D 3 receptors, and may also provide an opportunity for the synthesis of new radioligands for dopamine D 3 receptors. Dopamine D 3 receptors; Dopamine D 2 receptors; Dihydrexidine The dopamine D 3 receptor (Sokoloff et al., 1990) is a member of the dopamine 'D2-1ike' receptor family. Compared to the previously cloned dopamine D 2 receptors (D2s and D2L), the dopamine D 3 receptor appears to be much less abundant, and has a more restricted anatomical distribution. The majority of dopamine D 3 receptors and mRNA is found in limbic areas, including the olfactory tubercle, nucleus accumbens, islands of cajella and the hypothalamus (Sokoloff et al., 1990;. A major problem in understanding dopamine D 3 receptor pharmacology has been the limited number of selective ligands. The development of novel structural classes of D 3 selective ligands is essential for studying the pharmacophoric requirements of ligand-dopamine D 3 receptor interactions, and ultimately activation of dopamine D 3 receptors. In the present communication, we report a significant breakthrough in the development and initial characterization of a high affinity, D 3 selective class of ligands.
Journal of Medicinal Chemistry, 2006
The goal of this study was to identify a structurally distinct D 4 -selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein. s, were also synthesized from the arylpiperidine templates. Pyridine N-oxidation of the (2-pyridinyl)piperidine template would potentially deactivate the pyridine ring toward putative oxidation and meet the structural requirements of having meta and para hydrogen substituents on the region B aromatic ring for agonist activity. The (N-oxy-2-pyridinyl)piperidine template was utilized to conduct a second SAR study of region A to obtain benzamides 6a-s and acetamides 7a-z. In this report we describe the discovery of 6b (ABT-670) a novel, orally bioavailable, potent, and selective human dopamine D 4 receptor agonist.
Bioorganic & Medicinal Chemistry, 2010
A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D 2-like dopamine receptors. These compounds also share structural elements with the classical D 2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate were found to (a) bind to the D 2 receptor subtype with high affinity (K i values <0.3 nM), (b) exhibit >50-fold D 2 versus D 3 receptor binding selectivity and (c) be partial agonists at both the D 2 and D 3 receptor subtype.
European Journal of Medicinal Chemistry, 1999
With a straightforward seven-step synthesis, racemic perhydro benzoxazin-6-on was synthesized in overall good yields via regioselective epoxid ring-opening to the corresponding -aminoalcohol. The oxazine derivative was the key intermediate for the preparation of heteroaromatic analogues of the dopamine D 3 -receptor preferring agonist PD 128,907. The morpholine moiety of PD 128,907 was incorporated in diazole and diazine compounds obtained by different ring closure reactions. The target compounds obtained were structurally related to non-ergot heteroaromatic dopamine agonists which display preferential activity at the D 3 receptor, e.g., quinpirole, quinerolane, or pramipexole. The five membered aminothiazole, aminoselenazole, and pyrazole derivatives showed at least one order of magnitude higher binding at the human D 3 receptor than that at the D 2L receptor. Although the novel compounds displayed K i values only in the micromolar concentration range, the most active ones showed full agonist activity in a functional assay on mitogenesis. © 1999 Éditions scientifiques et médicales Elsevier SAS dopamine / D 3 -receptor / D 2 -receptor / PD 128,907 / agonist / mitogenesis / pramipexole / quinpirole / quinerolane