Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist

D. M. Mottola, W. K. Brewster, L. L. Cook, D. E. Nichols, Richard Mailman

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine), the first high-potency, full efficacy, bioavailable D1 dopamine receptor agonist. DHX represents a new conformationally rigid structural class of dopamine receptor ligands. It competes stereoselectively and potently for D1 binding sites in rat striatal membranes labeled with [3H]SCH23390 with an IC50 of about 10 nM compared to about 30 nM for the prototypical D1 agonist SKF38393. Like other dopamine agonists, DHX has a shallow competition curve (n(H) = ca. 0.7) that can be fitted by a two-site model consisting of high-affinity (63%; K(D) = 3 nM) and low-affinity (37%; K(D) = 75 nM) sites. DHX was screened for activity against 40 other binding sites, and was inactive (IC50 >10 μM) against all except D2 dopamine receptors (IC50 = 130 nM) and alpha2 adrenoreceptors (IC50 = ca. 230 nM). Functionally, DHX is a full efficacy dopamine D1 agonist. In homogenates of rat striatum, DHX or dopamine doubles the rate of cyclic AMP synthesis, whereas SKF38393 only causes a maximal increase of about 50%. These effects of DHX are blocked by the selective D1 antagonist SCH23390, but are not affected by D2, 5-hydroxytryptamine2, -muscarinic, or alpha or beta adrenergic antagonists. Because DHX is known to cause D2-like behavioral effects at high doses, the nature of its D2 activity was characterized using prolactin release as an end-point. DHX and the prototypical D2 agonist quinpirole both caused a significant inhibition of the prolactin release induced by 5-hydroxytryptophan. These effects of DHX are not due to 'indirect' alterations at the presynaptic terminal, because DHX is essentially inactive at inhibiting the dopamine uptake system, and does not cause the release of dopamine. These data demonstrate the utility of DHX for probing the biochemistry and function of D1 dopamine receptors.

Original languageEnglish (US)
Pages (from-to)383-393
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number1
StatePublished - 1992

Fingerprint

Dopamine Agonists
Inhibitory Concentration 50
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Dopamine
Prolactin
dihydrexidine
Phenanthridines
Binding Sites
Quinpirole
Adrenergic alpha-Antagonists
Corpus Striatum
5-Hydroxytryptophan
Dopamine D1 Receptors
Adrenergic beta-Antagonists
Dopamine D2 Receptors
Dopamine Receptors
Presynaptic Terminals
Biochemistry
Cyclic AMP
Cholinergic Agents

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Mottola, D. M., Brewster, W. K., Cook, L. L., Nichols, D. E., & Mailman, R. (1992). Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. Journal of Pharmacology and Experimental Therapeutics, 262(1), 383-393.
Mottola, D. M. ; Brewster, W. K. ; Cook, L. L. ; Nichols, D. E. ; Mailman, Richard. / Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. In: Journal of Pharmacology and Experimental Therapeutics. 1992 ; Vol. 262, No. 1. pp. 383-393.
@article{a004efdc7965413ab5ea39a22ed0b082,
title = "Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist",
abstract = "The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine), the first high-potency, full efficacy, bioavailable D1 dopamine receptor agonist. DHX represents a new conformationally rigid structural class of dopamine receptor ligands. It competes stereoselectively and potently for D1 binding sites in rat striatal membranes labeled with [3H]SCH23390 with an IC50 of about 10 nM compared to about 30 nM for the prototypical D1 agonist SKF38393. Like other dopamine agonists, DHX has a shallow competition curve (n(H) = ca. 0.7) that can be fitted by a two-site model consisting of high-affinity (63{\%}; K(D) = 3 nM) and low-affinity (37{\%}; K(D) = 75 nM) sites. DHX was screened for activity against 40 other binding sites, and was inactive (IC50 >10 μM) against all except D2 dopamine receptors (IC50 = 130 nM) and alpha2 adrenoreceptors (IC50 = ca. 230 nM). Functionally, DHX is a full efficacy dopamine D1 agonist. In homogenates of rat striatum, DHX or dopamine doubles the rate of cyclic AMP synthesis, whereas SKF38393 only causes a maximal increase of about 50{\%}. These effects of DHX are blocked by the selective D1 antagonist SCH23390, but are not affected by D2, 5-hydroxytryptamine2, -muscarinic, or alpha or beta adrenergic antagonists. Because DHX is known to cause D2-like behavioral effects at high doses, the nature of its D2 activity was characterized using prolactin release as an end-point. DHX and the prototypical D2 agonist quinpirole both caused a significant inhibition of the prolactin release induced by 5-hydroxytryptophan. These effects of DHX are not due to 'indirect' alterations at the presynaptic terminal, because DHX is essentially inactive at inhibiting the dopamine uptake system, and does not cause the release of dopamine. These data demonstrate the utility of DHX for probing the biochemistry and function of D1 dopamine receptors.",
author = "Mottola, {D. M.} and Brewster, {W. K.} and Cook, {L. L.} and Nichols, {D. E.} and Richard Mailman",
year = "1992",
language = "English (US)",
volume = "262",
pages = "383--393",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

Mottola, DM, Brewster, WK, Cook, LL, Nichols, DE & Mailman, R 1992, 'Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist', Journal of Pharmacology and Experimental Therapeutics, vol. 262, no. 1, pp. 383-393.

Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist. / Mottola, D. M.; Brewster, W. K.; Cook, L. L.; Nichols, D. E.; Mailman, Richard.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 1, 1992, p. 383-393.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dihydrexidine, a novel full efficacy D1 dopamine receptor agonist

AU - Mottola, D. M.

AU - Brewster, W. K.

AU - Cook, L. L.

AU - Nichols, D. E.

AU - Mailman, Richard

PY - 1992

Y1 - 1992

N2 - The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine), the first high-potency, full efficacy, bioavailable D1 dopamine receptor agonist. DHX represents a new conformationally rigid structural class of dopamine receptor ligands. It competes stereoselectively and potently for D1 binding sites in rat striatal membranes labeled with [3H]SCH23390 with an IC50 of about 10 nM compared to about 30 nM for the prototypical D1 agonist SKF38393. Like other dopamine agonists, DHX has a shallow competition curve (n(H) = ca. 0.7) that can be fitted by a two-site model consisting of high-affinity (63%; K(D) = 3 nM) and low-affinity (37%; K(D) = 75 nM) sites. DHX was screened for activity against 40 other binding sites, and was inactive (IC50 >10 μM) against all except D2 dopamine receptors (IC50 = 130 nM) and alpha2 adrenoreceptors (IC50 = ca. 230 nM). Functionally, DHX is a full efficacy dopamine D1 agonist. In homogenates of rat striatum, DHX or dopamine doubles the rate of cyclic AMP synthesis, whereas SKF38393 only causes a maximal increase of about 50%. These effects of DHX are blocked by the selective D1 antagonist SCH23390, but are not affected by D2, 5-hydroxytryptamine2, -muscarinic, or alpha or beta adrenergic antagonists. Because DHX is known to cause D2-like behavioral effects at high doses, the nature of its D2 activity was characterized using prolactin release as an end-point. DHX and the prototypical D2 agonist quinpirole both caused a significant inhibition of the prolactin release induced by 5-hydroxytryptophan. These effects of DHX are not due to 'indirect' alterations at the presynaptic terminal, because DHX is essentially inactive at inhibiting the dopamine uptake system, and does not cause the release of dopamine. These data demonstrate the utility of DHX for probing the biochemistry and function of D1 dopamine receptors.

AB - The present work provides a detailed pharmacological characterization of dihydrexidine (DHX) (trans-10,11-dihydroxy-5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine), the first high-potency, full efficacy, bioavailable D1 dopamine receptor agonist. DHX represents a new conformationally rigid structural class of dopamine receptor ligands. It competes stereoselectively and potently for D1 binding sites in rat striatal membranes labeled with [3H]SCH23390 with an IC50 of about 10 nM compared to about 30 nM for the prototypical D1 agonist SKF38393. Like other dopamine agonists, DHX has a shallow competition curve (n(H) = ca. 0.7) that can be fitted by a two-site model consisting of high-affinity (63%; K(D) = 3 nM) and low-affinity (37%; K(D) = 75 nM) sites. DHX was screened for activity against 40 other binding sites, and was inactive (IC50 >10 μM) against all except D2 dopamine receptors (IC50 = 130 nM) and alpha2 adrenoreceptors (IC50 = ca. 230 nM). Functionally, DHX is a full efficacy dopamine D1 agonist. In homogenates of rat striatum, DHX or dopamine doubles the rate of cyclic AMP synthesis, whereas SKF38393 only causes a maximal increase of about 50%. These effects of DHX are blocked by the selective D1 antagonist SCH23390, but are not affected by D2, 5-hydroxytryptamine2, -muscarinic, or alpha or beta adrenergic antagonists. Because DHX is known to cause D2-like behavioral effects at high doses, the nature of its D2 activity was characterized using prolactin release as an end-point. DHX and the prototypical D2 agonist quinpirole both caused a significant inhibition of the prolactin release induced by 5-hydroxytryptophan. These effects of DHX are not due to 'indirect' alterations at the presynaptic terminal, because DHX is essentially inactive at inhibiting the dopamine uptake system, and does not cause the release of dopamine. These data demonstrate the utility of DHX for probing the biochemistry and function of D1 dopamine receptors.

UR - http://www.scopus.com/inward/record.url?scp=0026643520&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026643520&partnerID=8YFLogxK

M3 - Article

C2 - 1352553

AN - SCOPUS:0026643520

VL - 262

SP - 383

EP - 393

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -