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.
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Martin A
authors.initials: MA
authors.lastname: Lewis
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Hunihan
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: John
authors.initials: J
authors.lastname: Watson
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gentles
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Shuanghua
authors.initials: S
authors.lastname: Hu
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Yazhong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Joanne
authors.initials: J
authors.lastname: Bronson
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Brett R
authors.initials: BR
authors.lastname: Beno
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Meredith
authors.initials: M
authors.lastname: Ferrante
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Adam
authors.initials: A
authors.lastname: Hendricson
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Knox
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Cvijic
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Rockwell
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weed
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Angela M
authors.initials: AM
authors.lastname: Cacace
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Westphal
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.affiliation: Bristol-Myers Squibb, Wallingford, Connecticut (M.A.L., L.H., J.W., R.G.G., S.H.,Y.H., J.B., B.R.B., M.F., A.H., R.J.K., T.F.M., K.L.R., M.R.W., A.M.C., A.A., J.M.B.); Bristol-Myers Squibb, Hopewell, New Jersey (Y.K., M.E.C.); Bristol-Myers Squibb, Lawrence Township, New Jersey (J.E.M.); and Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana (R.S.W.) jeffrey.brown@bms.com.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002478:Cells, Cultured; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2