title: Pharmacophore-guided drug discovery investigations leading to bioactive 5-aminotetrahydropyrazolopyridines. Implications for the binding mode of heterocyclic dopamine D3 receptor agonists.
abstract: Taking advantage of a 3D-QSAR based pharmacophore hypothesis, synthesis and biological evaluation of dopaminergic 5-aminotetrahydropyrazolo[1,5-a]pyridines are described. The data displayed substantial and selective D3 receptor affinity for the heterocyclic test compound (+/-)-1 when the enantiomer (S)-1 turned out to be responsible for the D3 binding (K(i) (high) = 4.0 nM). (S)-1 exhibited binding affinity and ligand efficacy comparable to those of our previously described D3 agonist FAUC 54, when subtype selectivity could be significantly improved. The results indicate that the sp(2) nitrogens of the pyrazole and thiazole rings of the dopaminergics (S)-1 and pramipexole, respectively, are pharmacophoric elements of major importance. To provide putative explanations for the high affinity of (S)-1, computational studies were performed employing an active state D3 model.
authors.affiliation: Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Elsner
authors.forename: Frank
authors.initials: F
authors.lastname: Boeckler
authors.forename: Frank W
authors.initials: FW
authors.lastname: Heinemann
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D001665:Binding Sites; D016466:CHO Cells; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D000077487:Pramipexole; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000737:chemistry; D050637:Receptors, Dopamine D3; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D052160:Benzothiazoles; D003510:Cyclohexanes; C493593:DRD3 protein, human; D018491:Dopamine Agonists; D011720:Pyrazoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D000077487:Pramipexole