Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands

Watts, Val J.; Lawler, Cindy P.; Knoerzer, Timm A.; Mayleben, Mechelle A.; Neve, Kim A.; Nichols, David E.; Mailman, Richard B.

doi:10.1016/0014-2999(93)91012-c

Cited by 30 publications

(9 citation statements)

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“…In the brain regions that were studied, the D 4 isoform is unlikely to be involved, yet the roles of the D 2L , D 2S , and D 3 receptors must be considered. DHX binds with similar affinity to both D 2L and D 2S in molecular expression systems, and can fully inhibit adenylate cyclase at both receptors (Watts et al, 1993b). Moreover, DHX competes similarly for D 2 receptor-labeled sites in striatum and substantia nigra, suggesting that DHX can bind to almost all D 2 -like sites, whether hetero-or autoreceptors.…”

Section: Discussionmentioning

confidence: 92%

“…Because some have suggested that D 3 receptors, although expressed at extremely low levels, serve as the primary dopamine autoreceptors (Aretha et al, 1995), it is possible that DHX fails to activate D 3 autoreceptors either by failing to bind or having low intrinsic efficacy (Meller et al, 1993;Kreiss et al, 1995). Yet, although quinpirole has some selectivity for D 3 /D 2 receptors, DHX is nonselective (Watts et al, 1993b). Apomorphine, which like DHX has no D 3 selectivity (Sokoloff et al, 1990), is able to activate D 2 autoreceptors fully.…”

Section: Discussionmentioning

confidence: 99%

“…Adenylate cyclase assays in rat striatal homogenates were performed as described by Watts et al (1993b). A 20-l aliquot of a 2.5-mg/ml homogenate solution was added to the reaction tubes.…”

Section: Adenylate Cyclase Assays In Rat Striatal Homogenatesmentioning

confidence: 99%

“…In addition to its properties as a high-affinity, full D 1 receptor agonist, DHX also has affinity for D 2 receptors similar to the prototypical D 2 receptor agonist quinpirole. Although there has been extensive characterization of the D 1 properties of DHX (Watts et al, 1993b, there is only preliminary data about the functional properties of DHX at D 2 receptors. These latter data suggest, however, that DHX has typical D 2 agonist properties, binding to both high-and low-affinity [ 3 H]spiperonelabeled sites, inhibiting prolactin release in vivo, and also inhibiting D 1 -stimulated cAMP efflux much like dopamine or other D 2 agonists (Mottola et al, 1992).…”

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confidence: 99%

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Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Mottola

Kilts

Lewis

et al. 2002

J Pharmacol Exp Ther

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114

107

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Dihydrexidine (DHX), the first high-affinity D 1 dopamine receptor full agonist, is only 10-fold selective for D 1 versus D 2 receptors, having D 2 affinity similar to the prototypical agonist quinpirole. The D 2 functional properties of DHX and its more D 2 selective analog N-n-propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D 2 receptors in rat striatum typical of D 2 agonists, binding to both high-and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D 2 receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D 2 receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D 2 sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D 2L and D 2S receptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed "functional selectivity") suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery. (D 2S ), D 3 , and D 4 . D 1 -like receptors preferentially recognize 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390) over benzamides (e.g., sulpiride), whereas the D 2 -like receptors have the opposite pharmacological specificity. D 1 -and D 2 -like receptors have been defined traditionally by their opposing effects on the enzyme adenylate cyclase, with D 1 receptors positively coupled to this enzyme, whereas D 2 receptors are either negatively coupled or uncoupled to this effector. More recently, the actions of dopamine D 1 -and D 2 -like receptors on signaling systems other than adenylate cyclase have been confirmed in a variety of systems, including coupling to G protein inwardly rectifying potassium channels, phosphatidylinositol hydrolysis, and voltage-activated calcium channels (Jaber et al., 1996).

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

“…Adenylate cyclase assays in rat striatal homogenates were performed as described by Watts et al (1993b). A 20-l aliquot of a 2.5-mg/ml homogenate solution was added to the reaction tubes.…”

Section: Adenylate Cyclase Assays In Rat Striatal Homogenatesmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Mottola

Kilts

Lewis

et al. 2002

J Pharmacol Exp Ther

Self Cite

114

107

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“…Quinoline derivatives are structural analogs of alkaloids [1], enzyme inhibitors [2], and antibiotics [3]; therefore, they should exhibit versatile biological activity. In addition, these compounds are good antioxidants [4] and antirads [5] for polymeric materials.…”

mentioning

confidence: 99%

Synthesis of benzo[f]quinoline derivatives by condensation of N-arylmethylene-2-naphthylamines with acetylcyclohexane and 1-acetylcyclohexene

Грачек

2004

Russ J Gen Chem

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N-Arylmethylene-2-naphthylamines react with acetylcyclohexane and 1-acetylcyclohexene under mild conditions to afford 2-aryl-2-(2-naphthylamino)ethyl cyclohexyl and 1-cyclohexenyl ketones, respectively. Under more severe conditions (110oC), the reaction is accompanied by cyclization with formation of 3-aryl-1-cyclohexyl (or 1-cyclohexenyl)benzo[ f ]quinolines. Proper choice of the amount of catalyst, temperature, and reaction time allows isolation of intermediate 3-aryl-1-cyclohexyl(or 1-cyclohexenyl)-3,4-dihydrobenzo[ f ]quinolines. Quinoline derivatives are structural analogs of alkaloids [1], enzyme inhibitors [2], and antibiotics [3]; therefore, they should exhibit versatile biological activity. In addition, these compounds are good antioxidants [4] and antirads [5] for polymeric materials. Interest in quinoline derivatives and analogs continuously increases. Some benzoquinolines were found to possess good complexing [6] and fluorescent properties [7].A known procedure for the synthesis of benzo[ f ]-quinolines is based on the condensation of Schiff bases derived from 2-naphthylamine with various aliphatic, aromatic, and heterocyclic methyl ketones [8312]. It was found that the formation of benzo[ f ]-quinolines is a multistep process [12]. The reaction of N-arylmethylene-2-naphthylamines with methyl ketones of the cycloaliphatic series has been studied poorly. We previously synthesized benzo[ f ]quinoline derivatives by condensation of N-arylmethylene-2-naphthylamines with acetylcyclohexane and 1-acetylcyclohexene [13,14]. In doing so, either no intermediate products were isolated at all or they were isolated in very small amounts. In the present work we performed condensations of acetylcyclohexane (I) and 1-acetylcyclohexene (II) with Schiff bases IIIa3 IIIh of the 2-naphthylamine series using larger amounts of the initial reactants and tried to isolate and examine intermediate products by varying the reaction conditions.Condensations of Schiff bases with ketones are catalyzed by acids. Proton addition to a Schiff base yields the corresponding cation in which the positive charge is delocalized over the azomethine nitrogen and carbon atoms. Therefore, such cations readily take up even weakly nucleophilic ketones. The reaction mechanism is analogous to the acid-catalyzed aldol addition pattern. The reaction involves the methyl group in methyl ketone, so that the latter acts as CH acid. Amino ketones IVa3IVf and Va3Vg thus formed are the first intermediate products in the synthesis of benzo[ f ]quinolines (see scheme). The double bond in 1-acetylcyclohexene is conjugated with the carbonyl group; as a result, polarization of the C=O bond increases, and protons in the acetyl group become more labile. Therefore, the yields of amino ketones from 1-acetylcyclohexene are greater, and the condensation occurs at a lower temperature, as compared to acetylcyclohexane (Table 1). Amino ketones IVa3IVf and Va3Vg were obtained by heating the reactants in ethanol at 40360oC in the presence of a catalytic amount of hydrochlor...

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Molecular Biology of Dopamine Receptors

Neve¹,

Neve²

1997

The Dopamine Receptors

127

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Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands

Cited by 30 publications

References 3 publications

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Synthesis of benzo[f]quinoline derivatives by condensation of N-arylmethylene-2-naphthylamines with acetylcyclohexane and 1-acetylcyclohexene

Molecular Biology of Dopamine Receptors

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Hexahydrobenzo[a]phenanthridines: novel dopamine D3 receptor ligands

Cited by 30 publications

References 3 publications

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2Receptors Linked to Adenylate Cyclase

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D2Receptors Linked to Adenylate Cyclase

Synthesis of benzo[f]quinoline derivatives by condensation of N-arylmethylene-2-naphthylamines with acetylcyclohexane and 1-acetylcyclohexene

Molecular Biology of Dopamine Receptors

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Product

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Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase

Functional Selectivity of Dopamine Receptor Agonists. I. Selective Activation of Postsynaptic Dopamine D₂Receptors Linked to Adenylate Cyclase