TY - JOUR
T1 - Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A
AU - Zhang, Zhanbin
AU - Lu, Xiaoxia
AU - Xu, Jinbin
AU - Rothfuss, Justin
AU - MacH, Robert H.
AU - Tu, Zhude
N1 - Funding Information:
1 H NMR and 13 C NMR spectra were recorded on a Varian 300 MHz NMR spectrometer. Chemical shifts were reported in δ values with respect to tetramethylsilane (TMS) as an internal reference standard. The following abbreviations are used for multiplicity of NMR signals: br s = broad singlet, s = singlet, d = doublet, dd = doublet of doublets, dt = doublet of triplet, t = triplet, m = multiplet, q = quartet. Melting points were determined on an electrothermal melting point apparatus and were uncorrected. Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA, and were within ±0.4% of the calculated values. Mass spectrometry was provided by the Washington University Mass Spectrometry Resource, an NIH Research Resource (Grant No. P41RR0954). All reactions were carried out under an inert atmosphere of nitrogen.
Funding Information:
Financial support for these studies was provided by the National Institute of Health under MH081281-04 (PI: Mach), NS061025 (PI: Tu) and MH092797 (PI: Tu).
PY - 2011/9
Y1 - 2011/9
N2 - A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC 50) values for these new analogues were measured; for compounds that have IC 50 value less than 60 nM for PDE10A, the binding affinities (IC 50 value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC 50 value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)- 3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC 50 value of 28 ± 1.2 nM for PDE10A, 2200 ± 437 nM for PDE3A and 2520 ± 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.
AB - A series of analogues were synthesized by optimizing the structure of papaverine. The in vitro PDE10A binding affinity (IC 50) values for these new analogues were measured; for compounds that have IC 50 value less than 60 nM for PDE10A, the binding affinities (IC 50 value) for PDE3A and PDE3B were tested. Of these analogues, compounds 6a, 6b, 6n, 8b, 8c and 11 displayed relatively higher PDE10A potency with IC 50 value in the range of 28-60 nM. The most potent compound 1-(4-(2-(2-fluoroethoxy)ethoxy)- 3-methoxybenzyl)-6,7-dimethoxyisoquinoline (8c) has the IC 50 value of 28 ± 1.2 nM for PDE10A, 2200 ± 437 nM for PDE3A and 2520 ± 210 nM for PDE3B. Compared to papaverine, compound 8c displayed similar PDE10A potency but improved selectivity to PDE10A versus PDE3A and PDE3B. To identify high potent PDE10A inhibitor, further optimization of the structures of these analogues is necessary.
KW - CNS
KW - PDE10A
KW - Schizophrenia
UR - https://www.scopus.com/pages/publications/80052918961
U2 - 10.1016/j.ejmech.2011.05.072
DO - 10.1016/j.ejmech.2011.05.072
M3 - Article
C2 - 21705115
AN - SCOPUS:80052918961
SN - 0223-5234
VL - 46
SP - 3986
EP - 3995
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 9
ER -