Harmful:;143592-06-7Relevant articles and documents
Pyrroloquinoxaline derivatives as high-affinity and selective 5-HT3 receptor agonists: Synthesis, further structure-activity relationships, and biological studies
Campiani, Giuseppe,Morelli, Elena,Gemma, Sandra,Nacci, Vito,Butini, Stefania,Hamon, Michel,Novellino, Ettore,Greco, Giovanni,Cagnotto, Alfredo,Goegan, Mara,Cervo, Luigi,Valle, Fabio Dalla,Fracasso, Claudia,Caccia, Silvio,Mennini, Tiziana
, p. 4362 - 4379 (2007/10/03)
The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel pyrroloquinoxalines and heteroaromatic-related derivatives are described. The new pyrroloquinoxaline- related ligands were tested in rat cortex, a tissue expressing high density of 5-HT3 receptors, and on NG108-15 cells and exhibited IC50 values in the low nanomolar or subnanomolar range, as measured by the inhibition of [3H]zacopride binding. The SAR studies detailed herein delineated a number of structural features required for improving affinity. Some of the ligands were employed as 'molecular yardsticks' to probe the spatial dimensions of the lipophilic pockets L1, L2, and L3 in the 5-HT3 receptor cleft, while the 7-OH pyrroloquinoxaline analogue was designed to investigate hydrogen bonding with a putative receptor site H1 possibly interacting with the serotonin hydroxy group. The most active pyrroloquinoxaline derivatives showed subnanomolar affinity for the 5-HT3 receptor. In functional studies ([14C]guanidinium accumulation test in NG108-15 hybrid cells, in vitro) most of the tested compounds showed clear-cut 5-HT3 agonist properties, while some others were found to be partial agonists. Several heteroaromatic systems, bearing N-substituted piperazine moieties, have been explored with respect to 5-HT3 affinity, and novel structural leads for the development of potent and selective central 5-HT3 receptor agonists have been identified. Preliminary pharmacokinetic studies indicate that these compounds easily cross the blood brain barrier (BBB) after systemic administration with a brain/plasma ratio between 2 and 20, unless they bear a highly hydrophilic group on the piperazine ring. None of the tested compounds showed in vivo anxiolytic-like activity, but potential analgesic-like properties have been possibly disclosed for this new class of 5-HT3 receptor agonists.
Synthesis and Hypoglycemic Activity of Substituted 8-(1-Piperazinyl)imidazopyrazines
Meurer, Laura C.,Tolman, Richard L.,Chapin, Edward W.,Saperstein, Richard,Vicario, Pasquale P.,et al.
, p. 3845 - 3857 (2007/10/02)
A series of alkyl- and halo-substituted 8-(1-piperazinyl)imidazopyrazines were prepared using two approaches, the condensation of α-halocarbonyl derivatives with an aminopyrazine or the oxidation-dehydration of a pyrazine.These imidazopyrazines were evaluated for their binding affinity to the α1, α2, β1, and β2 adrenergic receptors as well as their ability to lower blood glucose in insulin resistant hyperglycemic ob/ob mice.Modifications on 8-(1-piperazinyl)imidazopyrazine (4) reduced α2 binding, lowered hyoglycemic potency, and showed variations in binding to the α1, β1, and β2 adrenergic receptors.In addition to 4, the 2-methyl, 3-methyl, and 5-methyl 8-(1-piperazinyl)imidazopyrazines (16k, 25m, and 16f, respectively) displayed high affinity for the α2 receptor and were potent hypoglycemic agents when compared to 2-amino-7,8-dihydro-4-(1-piperazinyl)-6H-thiopyranopyrimidine (MTP-1403, 2).Receptor binding was modified by use of a 4-methylpiperazine moiety which reduced α1 and β1 binding while retaining some hypoglycemic activity.The structure-activity relationship for heterocyclic alkyl and halo substitution on biological activity is discussed.
