Dopaminergic Benzo[a]phenanthridines: Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist

Timm A. Knoerzer, David E. Nichols, William K. Brewster, Val J. Watts, David Mottola, Richard Mailman

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Racemic trans-10,11-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-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,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 [3H]SCH23390 (K0.5S 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 EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 μM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 μM 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.

Original languageEnglish (US)
Pages (from-to)2453-2460
Number of pages8
JournalJournal of Medicinal Chemistry
Volume37
Issue number15
DOIs
StatePublished - Jul 1 1994

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Phenanthridines
Corpus Striatum
Dopamine Agonists
Pharmacology
Spiperone
Dopamine D1 Receptors
Membranes
Dopamine D2 Receptors
Adenylyl Cyclases
Amides
Amines
Chromatography
Dopamine
Binding Sites
X-Rays
Ligands
Acids
dihydrexidine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Knoerzer, Timm A. ; Nichols, David E. ; Brewster, William K. ; Watts, Val J. ; Mottola, David ; Mailman, Richard. / Dopaminergic Benzo[a]phenanthridines : Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 15. pp. 2453-2460.
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Dopaminergic Benzo[a]phenanthridines : Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist. / Knoerzer, Timm A.; Nichols, David E.; Brewster, William K.; Watts, Val J.; Mottola, David; Mailman, Richard.

In: Journal of Medicinal Chemistry, Vol. 37, No. 15, 01.07.1994, p. 2453-2460.

Research output: Contribution to journalArticle

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T2 - Resolution and Pharmacological Evaluation of the Enantiomers of Dihydrexidine, the Full Efficacy D1 Dopamine Receptor Agonist

AU - Knoerzer, Timm A.

AU - Nichols, David E.

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AU - Mottola, David

AU - Mailman, Richard

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N2 - Racemic trans-10,11-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-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,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 [3H]SCH23390 (K0.5S 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 EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 μM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 μM 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.

AB - Racemic trans-10,11-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-10,11-dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine 4 that were then separated by centrifugal chromatography. An X-ray analysis of the (-)-N-(R)-O-methylmandel diastereoamide revealed the absolute configuration to be 6aS,12bR. Removal of the chiral auxiliary and O,O-deprotection afforded enantiomeric amines that were then tested for biological activity. In striatal membranes, the (6aR,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 [3H]SCH23390 (K0.5S 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 EC50 of 51 nM in activating striatal dopamine-sensitive adenylate cyclase versus 2.15 μM for the (-)-enantiomer. With respect to D2-like receptors, (+)-2 had a K0.5 of 87.7 nM in competing with [3H]spiperone at D2 binding sites in rat striatal membranes versus about 1 μM 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.

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