Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease.
During a program to investigate the biochemical basis of side effects associated with the antimalarial drug mefloquine, the authors made the unexpected discovery that the (-)-(R,S)-enantiomer of the drug is a potent adenosine A2A receptor antagonist. Although the compound was ineffective in in vivo animal models of central adenosine receptor function, it provided a unique nonxanthine adenosine A2A receptor antagonist lead structure and encouraged the initiation of a medicinal chemistry program to develop novel adenosine A2A antagonists for the management of Parkinson's disease (PD). The authors have synthesized and screened more than 2,000 chemically diverse and novel adenosine A(2A antagonists. Early examples from two distinct chemical series are the thieno[3,2-dy]pyrimidine VER-6623 and the purine compounds VER-6947 and VER-7835, which have high affinity at adenosine A2A receptors (K(i) values 1.4, 1.1, and 1.7 nmol/L, respectively) and act as competitive antagonists. In particular, VER-6947 and VER-7835 demonstrate potent in vivo activity reversing the locomotor deficit caused by the D2 receptor antagonist haloperidol, with minimum effective doses comparable with that of KW6002 (0.3 to 1 mg/kg). In conclusion, the authors have discovered potent, selective, and in vivo active nonxanthine adenosine A2A antagonists that have considerable promise as a new therapy for PD.
Weiss
S M
SM
Vernalis Research Ltd., Wokingham, UK. s.weiss@vernalis.com
Benwell
K
K
Cliffe
I A
IA
Gillespie
R J
RJ
Knight
A R
AR
Lerpiniere
J
J
Misra
A
A
Pratt
R M
RM
Revell
D
D
Upton
R
R
Dourish
C T
CT
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000737:chemistry / Q000627:therapeutic use*; D001667:Binding, Competitive / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D015767:Mefloquine / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D010627:Phenethylamines / Q000737:chemistry / Q000627:therapeutic use; D011687:Purines / Q000737:chemistry / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use*; D011869:Radioligand Assay; D051381:Rats; D014227:Triazines / Q000737:chemistry / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry / Q000627:therapeutic use
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D008024:Ligands; D018696:Neuroprotective Agents; D010627:Phenethylamines; D011687:Purines; D011743:Pyrimidines; D014227:Triazines; D014230:Triazoles; C481343:VER6623; C481344:VER6947; C481345:VER7835; C097270:ZM 241385; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C111599:istradefylline; D000241:Adenosine; D015767:Mefloquine