ABSTRACT
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Subject(s)
Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/physiology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Cyclooxygenase 2 Inhibitors/therapeutic use , Indicators and Reagents , Joints/pathology , Lactones/therapeutic use , Osteoarthritis/chemically induced , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity Relationship , Sulfones/therapeutic useABSTRACT
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Subject(s)
Drug Design , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Models, Molecular , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
Previously, we reported on PD 102807 (41) as being the most selective synthetic M(4) muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M(4) receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pK(i) = 9.00 at M(4) receptors and a selectivity of M(1)/M(4) = 13 183-fold, M(2)/M(4) = 339-fold, M(3)/M(4) = 151-fold, and M(5)/M(4) = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M(4) antagonists such as the M(4) selective Eastern Green Mamba venom MT3 (M(4) pK(b) = 8.7, M(1)/M(4) = 40-fold, M(2)/M(4) > or = 500-fold, M(3)/M(4) > or = 500-fold, and M(5)/M(4) > or = 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M(1)/M(4) selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M(4) receptors.
