Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor

DeNinno, Michael P.; Schoenleber, Robert; Perner, Richard J.; Lijewski, Linda; Asin, Karen E.; Britton, Donald R.; MacKenzie, Robert G.; Kebabian, John W.

doi:10.1021/jm00112a034

Cited by 63 publications

(47 citation statements)

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“…However, using homogenate of rat striatum, we could only detect the effect of D 1 receptors on AC activity. All the agonists of D 1 receptors tested resulted in a concentration-dependent activation of cAMP accumulation with EC 50 values being in agreement with the potencies reported earlier for striatal membranes (23,24 (7) has been used to observe changes in signal transduction of D 2 receptors caused by dopaminergic denervation with 6-OHDA (25) or partial noradrenergic denervation with DSP-4 (26,27), as well as by manipulation of animals (12).…”

Section: Discussionsupporting

confidence: 86%

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

2008

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Abstract. We have characterized the modulation of adenylyl cyclase (AC) activity by ligands of dopaminergic receptors in rat striatal homogenate and compared the results with receptorligand binding affinities. Despite the fact that rat striatum contains high level of both dopamine D 1 and D 2 receptors, only the D 1 -specific AC activation by agonists could be determined. All D 1 -receptor agonists (dopamine, dihydrexidine, and A 77636) used were able to increase cAMP accumulation in a concentration-dependent manner, while D 1 -receptor antagonists (SCH23390, SKF83566, and butaclamol) blocked the effects induced by the aforementioned agonists. At the same time, the D 2 -receptor agonist quinpirole and antagonist sulpiride had no effect on cAMP accumulation in striatal homogenate neither on the basal level nor on the activated level of AC, while inhibited [

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Section: Discussionsupporting

confidence: 86%

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

2008

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“…Abbott Laboratories had developed bicyclic isochroman ligands with high-affinity and selectivity for D 1 -like receptors (DeNinno et al, 1991). A variety of hydrophobic substituents at the C3 position of the isochromans increase D 1 -like selectivity, presumably by interacting with the same accessory binding region that is exploited by the ␤-phenyl moiety that is common to many D 1 receptor-selective agonists (Nichols, 2010).…”

Section: Discussionmentioning

confidence: 99%

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D₁Receptor Catechol Agonists

Chemel¹,

Bonner²,

Watts³

et al. 2012

Mol Pharmacol

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To refine further the structure-activity relationships of D 1 dopamine receptor agonists, we investigated the roles of three conserved serine residues [Ser198(5.42), Ser199(5.43), and Ser202(5.46)] in agonist binding and receptor activation. These transmembrane domain 5 (TM5) residues are believed to engage catechol ligands through polar interactions. We stably expressed wild-type or mutant (S198A, S199A, and S202A) D 1 receptors in human embryonic kidney cells. These receptors were expressed at similar levels (approximately 2000 fmol/mg) and bound the radioligand [3 H]R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH 23390), although S198A and S199A displayed significant losses of affinity compared with that for wild-type receptors. The endogenous agonist, dopamine, had losses of potency at each of the mutant receptors. We tested cyclohexyl-substituted isochroman, carbocyclic, and chroman bicyclic dopamine analogs and found that the mutations affected the chroman to a lesser extent than the other compounds. These results support our hypothesis that the decreased D 1 activity of chroman analogs results from a ligand intramolecular hydrogen bond that impairs the ability of the catechol to engage the receptor. Sensitivities of these rigid catechol agonists to the effects of the serine mutations were dependent on ligand geometry, particularly with respect to the rotameric conformation of the ethylamine side chain and the distance between the amino group and each catechol hydroxyl. Functional experiments in striatal tissue suggest that the ability to engage TM5 serines is largely correlated with agonist efficacy for cAMP stimulation. These results provide a new understanding of the complexities of D 1 ligand recognition and agonist activation and have implications for the design of rigid catechol ligands.

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“…The final class of agonists is the isochromans (Fig. 1), from which A68930 and A77636 were developed (DeNinno et al, 1990(DeNinno et al, , 1991. All three classes of D 1 agonists have docking and activation modes that are relatively similar (Mottola et al, 1996).…”

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confidence: 99%

Differential Activation of Adenylate Cyclase and Receptor Internalization by Novel Dopamine D₁ Receptor Agonists

Ryman-Rasmussen

Nichols

Mailman³

2005

Mol Pharmacol

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Structurally dissimilar dopamine D 1 receptor agonists were compared with dopamine in their ability to activate adenylate cyclase and to internalize hemagglutinin-tagged human D 1 receptors in a stably transfected human embryonic kidney cell line. Thirteen dopamine D 1 receptor agonists were selected rationally from three different structural classes: rigid fused ring compounds [dihydrexidine, dinapsoline, dinoxyline, apomorphine, and (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]-phenanthrene-9,

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Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor

Cited by 63 publications

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Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D₁Receptor Catechol Agonists

Differential Activation of Adenylate Cyclase and Receptor Internalization by Novel Dopamine D₁ Receptor Agonists

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Synthesis and dopaminergic activity of 3-substituted 1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyrans: characterization of an auxiliary binding region in the D1 receptor

Cited by 63 publications

References 0 publications

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D1Receptor Catechol Agonists

Differential Activation of Adenylate Cyclase and Receptor Internalization by Novel Dopamine D1 Receptor Agonists

Contact Info

Product

Resources

About

Ligand-Specific Roles for Transmembrane 5 Serine Residues in the Binding and Efficacy of Dopamine D₁Receptor Catechol Agonists

Differential Activation of Adenylate Cyclase and Receptor Internalization by Novel Dopamine D₁ Receptor Agonists