ABSTRACT
A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhibited extremely high affinity and selectivity for the NOP receptor and showed full agonist activity, as determined by stimulation of GTPgamma[35S] binding.
Subject(s)
Receptors, Opioid, mu/agonists , Thiazines/chemical synthesis , Thiazoles/chemical synthesis , Animals , Humans , In Vitro Techniques , Ligands , Radioligand Assay , Rats , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship , Thiazines/chemistry , Thiazines/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Subject(s)
Analgesics/chemical synthesis , Pyridines/chemical synthesis , Sodium Channel Blockers/chemical synthesis , Analgesics/chemistry , Analgesics/pharmacology , Animals , Animals, Newborn , Brain/metabolism , Cell Line , Humans , In Vitro Techniques , Male , NAV1.2 Voltage-Gated Sodium Channel , Nerve Tissue Proteins/antagonists & inhibitors , Pain/drug therapy , Pain/physiopathology , Pain Measurement , Peripheral Nervous System Diseases/physiopathology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sodium Channels , Structure-Activity RelationshipABSTRACT
Small molecule N/OFQ receptor antagonists were designed and synthesized to further investigate the therapeutic potential of N/OFQ receptor modulators. The resulting octahydrobenzimidazol-2-ones 14 and 23 show excellent antagonistic activity towards both N/OFQ and mu receptors with high affinity to the human N/OFQ receptor.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Drug Design , Narcotic Antagonists , Piperidines/chemical synthesis , Piperidines/pharmacology , Humans , Protein Binding , Receptors, Opioid , Nociceptin ReceptorABSTRACT
[reaction: see text]. A stereocontrolled synthesis of quinolizidine 1, the reported structure of plumerinine, has been accomplished in 10 steps from 4-methoxypyridine. The key step is a highly facial selective intramolecular [2 + 2] photocycloaddition of a 2,3-dihydro-4-pyridone. The reported spectral data for plumerinine did not match that of our synthetic 1.