ABSTRACT
We designed and synthesized novel δ opioid receptor (DOR) agonists 3a-i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects.
Subject(s)
Analgesics, Opioid/pharmacology , Analgesics, Opioid/pharmacokinetics , Blood-Brain Barrier/metabolism , Cyclodecanes/pharmacology , Cyclodecanes/pharmacokinetics , Receptors, Opioid, delta/agonists , Administration, Cutaneous , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Animals , Cyclodecanes/chemical synthesis , Cyclodecanes/chemistry , Drug Design , Humans , Mice , Receptors, Opioid, delta/metabolismABSTRACT
An efficient synthesis of the tricyclo[4,3,1,0(1, 5)]decane core (B/C/D rings) of plumisclerin A, a unique cytotoxic marine diterpenoid, is described. A Pauson-Khand reaction and a SmI2-mediated radical 1,4-conjugate addition successfully served as key reactions for construction of the fully functionalized 5,6-fused rings and the highly strained cyclobutanol moiety with correct relative stereochemistries, respectively.
Subject(s)
Cyclodecanes/chemical synthesis , Diterpenes/chemical synthesis , Cyclization , Cyclodecanes/chemistry , Diterpenes/chemistry , Molecular Structure , StereoisomerismABSTRACT
A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1â¼3,7â¼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
Subject(s)
Aza Compounds/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Cyclodecanes/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , Aza Compounds/chemistry , Aza Compounds/pharmacology , Biological Availability , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Crystallography, X-Ray , Cyclodecanes/chemistry , Cyclodecanes/pharmacology , Dogs , Drug Design , Humans , Male , Microsomes, Liver/metabolism , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, G-Protein-Coupled/chemistry , Solubility , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1(2,5)]decane (1a) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.0(3,8)]decane (2a), in which the cinnamyl moiety was replaced by various aralkenyl chains, 1b-l and 2b-l, respectively, have been synthesized and evaluated for their ability to bind to the opioid mu-, delta- and kappa-receptors. The binding data indicated that compounds 1b,d,e,h and 2b,d,e,f,h,i showed a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. Selected DTDs, the pairs 1,2b, 1,2e and 1,2h, were also evaluated for analgesic effect. In the hot plate test, only 1b given ip was found to have similar opioid antinociception and chronic tolerance as morphine.
