Synthesis and Biological Evaluation of a Series of Substituted Benzo[α]phenanthridines as Agonists at D1 and D2 Dopamine Receptors

Timm A. Knoerzer, Val J. Watts, David E. Nichols, Richard B. Mailman

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Dihydrexidine [4; (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (±)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (5) was a high-affmity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[α]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.

Original languageEnglish (US)
Pages (from-to)3062-3070
Number of pages9
JournalJournal of Medicinal Chemistry
Volume38
Issue number16
DOIs
StatePublished - Aug 1 1995

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Phenanthridines
Dopamine D1 Receptors
Dopamine D2 Receptors
Pharmacology
Drug Receptors
Alkylation
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

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title = "Synthesis and Biological Evaluation of a Series of Substituted Benzo[α]phenanthridines as Agonists at D1 and D2 Dopamine Receptors",
abstract = "Dihydrexidine [4; (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (±)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (5) was a high-affmity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[α]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.",
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Synthesis and Biological Evaluation of a Series of Substituted Benzo[α]phenanthridines as Agonists at D1 and D2 Dopamine Receptors. / Knoerzer, Timm A.; Watts, Val J.; Nichols, David E.; Mailman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 38, No. 16, 01.08.1995, p. 3062-3070.

Research output: Contribution to journalArticle

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N2 - Dihydrexidine [4; (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (±)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (5) was a high-affmity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[α]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.

AB - Dihydrexidine [4; (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (DHX)], the first high-affinity full D1 agonist, also is known to have significant D2 activity. The present work reports the synthesis and pharmacological activity of a series of analogs substituted in the pendent phenyl ring (i.e., 2-, 3-, or 4-position). (±)-trans-2-Methyl-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[α]phenanthridine (5) was a high-affmity D1 agonist, having approximately 4-fold greater D1 vs D2 selectivity than DHX itself. All of the analogs containing a methyl or ethyl (but not a phenyl) substituent at the 2-, 3-, or 4-position had a pharmacological profile similar to that of the lead compound DHX (4). Each analog was found to be a high-affinity full agonist with moderate selectivity for the D1 receptor. It is apparent from these results that the D1 receptor can tolerate small substituents at the 2-, 3-, and 4-positions of the pendent phenyl ring. On the basis of earlier studies showing that N-alkylation increases D2 selectivity, the 3-methyl N-n-propyl and 4-methyl N-n-propyl compounds 11 and 13 were synthesized. While these analogs exhibited much higher affinity for the D2 receptor, surprisingly 4-methyl-N-propyl-DHX (13) exhibited high affinity for both the D1 and D2 receptors. It was subsequently established that this compound is a selective D3 ligand (110-fold selectivity for the D3 over D2 receptor). The results from these studies demonstrate that several of the hexahydrobenzo[α]phenanthridine derivatives are agonists with high intrinsic activity that may serve as powerful tools to explore the structural features that determine affinity and selectivity (relative to the D2 receptor) of drugs for D1 receptors.

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