Discovery of D1 dopamine receptor positive allosteric modulators: Characterization of pharmacology and identification of residues that regulate species selectivity

Martin A. Lewis, Lisa Hunihan, John Watson, Robert G. Gentles, Shuanghua Hu, Yazhong Huang, Joanne Bronson, John E. Macor, Brett R. Beno, Meredith Ferrante, Adam Hendricson, Ronald J. Knox, Thaddeus F. Molski, Yan Kong, Mary Ellen Cvijic, Kristin L. Rockwell, Michael R. Weed, Angela M. Cacace, Ryan S. Westphal, Andrew AltJeffrey M. Brown

Research output: Contribution to journalArticle

Abstract

The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol- 5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl) piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3- methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene- 12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.

Original languageEnglish (US)
Pages (from-to)340-349
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume354
Issue number3
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint

Dopamine D1 Receptors
Pharmacology
Amino Acids
Dopamine D2 Receptors
Primates
Molecular Biology
Rodentia
Dopamine
Schizophrenia
Pharmacokinetics
Kidney
Therapeutics
piperazine

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Medicine(all)

Cite this

Discovery of D1 dopamine receptor positive allosteric modulators : Characterization of pharmacology and identification of residues that regulate species selectivity. / Lewis, Martin A.; Hunihan, Lisa; Watson, John; Gentles, Robert G.; Hu, Shuanghua; Huang, Yazhong; Bronson, Joanne; Macor, John E.; Beno, Brett R.; Ferrante, Meredith; Hendricson, Adam; Knox, Ronald J.; Molski, Thaddeus F.; Kong, Yan; Cvijic, Mary Ellen; Rockwell, Kristin L.; Weed, Michael R.; Cacace, Angela M.; Westphal, Ryan S.; Alt, Andrew; Brown, Jeffrey M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 354, No. 3, 01.09.2015, p. 340-349.

Research output: Contribution to journalArticle

Lewis, MA, Hunihan, L, Watson, J, Gentles, RG, Hu, S, Huang, Y, Bronson, J, Macor, JE, Beno, BR, Ferrante, M, Hendricson, A, Knox, RJ, Molski, TF, Kong, Y, Cvijic, ME, Rockwell, KL, Weed, MR, Cacace, AM, Westphal, RS, Alt, A & Brown, JM 2015, 'Discovery of D1 dopamine receptor positive allosteric modulators: Characterization of pharmacology and identification of residues that regulate species selectivity', Journal of Pharmacology and Experimental Therapeutics, vol. 354, no. 3, pp. 340-349. https://doi.org/10.1124/jpet.115.224071
Lewis, Martin A. ; Hunihan, Lisa ; Watson, John ; Gentles, Robert G. ; Hu, Shuanghua ; Huang, Yazhong ; Bronson, Joanne ; Macor, John E. ; Beno, Brett R. ; Ferrante, Meredith ; Hendricson, Adam ; Knox, Ronald J. ; Molski, Thaddeus F. ; Kong, Yan ; Cvijic, Mary Ellen ; Rockwell, Kristin L. ; Weed, Michael R. ; Cacace, Angela M. ; Westphal, Ryan S. ; Alt, Andrew ; Brown, Jeffrey M. / Discovery of D1 dopamine receptor positive allosteric modulators : Characterization of pharmacology and identification of residues that regulate species selectivity. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 354, No. 3. pp. 340-349.
@article{b7f146facdb745228aef0bc360087dbd,
title = "Discovery of D1 dopamine receptor positive allosteric modulators: Characterization of pharmacology and identification of residues that regulate species selectivity",
abstract = "The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol- 5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl) piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3- methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene- 12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.",
author = "Lewis, {Martin A.} and Lisa Hunihan and John Watson and Gentles, {Robert G.} and Shuanghua Hu and Yazhong Huang and Joanne Bronson and Macor, {John E.} and Beno, {Brett R.} and Meredith Ferrante and Adam Hendricson and Knox, {Ronald J.} and Molski, {Thaddeus F.} and Yan Kong and Cvijic, {Mary Ellen} and Rockwell, {Kristin L.} and Weed, {Michael R.} and Cacace, {Angela M.} and Westphal, {Ryan S.} and Andrew Alt and Brown, {Jeffrey M.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1124/jpet.115.224071",
language = "English (US)",
volume = "354",
pages = "340--349",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Discovery of D1 dopamine receptor positive allosteric modulators

T2 - Characterization of pharmacology and identification of residues that regulate species selectivity

AU - Lewis, Martin A.

AU - Hunihan, Lisa

AU - Watson, John

AU - Gentles, Robert G.

AU - Hu, Shuanghua

AU - Huang, Yazhong

AU - Bronson, Joanne

AU - Macor, John E.

AU - Beno, Brett R.

AU - Ferrante, Meredith

AU - Hendricson, Adam

AU - Knox, Ronald J.

AU - Molski, Thaddeus F.

AU - Kong, Yan

AU - Cvijic, Mary Ellen

AU - Rockwell, Kristin L.

AU - Weed, Michael R.

AU - Cacace, Angela M.

AU - Westphal, Ryan S.

AU - Alt, Andrew

AU - Brown, Jeffrey M.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol- 5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl) piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3- methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene- 12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.

AB - The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol- 5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl) piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3- methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene- 12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.

UR - http://www.scopus.com/inward/record.url?scp=84941555410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941555410&partnerID=8YFLogxK

U2 - 10.1124/jpet.115.224071

DO - 10.1124/jpet.115.224071

M3 - Article

C2 - 26109678

AN - SCOPUS:84941555410

VL - 354

SP - 340

EP - 349

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -