The first series of compounds, 4a 4f and 5a 5f, showed modest receptor affinity for the A3AR with Ki values in the low to mid μM range.
In vitro competition binding assays against sigma proteins (sigma-1 S1R and sigma-2 S2revealedled that most of them conferred S2R/S1R selectivity toward without cytotoxic effects on SY5Y cells, especially with the first series with compounds 7a-z.
The comparison of the results obtained from the two series of samples permitted the assignment of γ, β and ω relaxations, observed in the first series of compounds, to motions of non-conjugated CO groups, CO groups located between a phenyl ring and a flexible lactam-12 or methylpentane sequence, and CO groups situated between a phenyl ring and a rigid cycloaliphatic moiety, respectively.
The first series of compounds (A1 A54) was less potent than the other two series but exhibited significant pancreatic lipase inhibitory activities (Table 1).
In a first series of compounds, this substituent was replaced with aromatic and heteroaromatic rings.
The first series of compounds 37a– d (Table 4) were prepared based on the cycloSal nucleotide approach.
Among the first series of compounds 5– 10, replacement of a piperazine moiety by a methylpiperidine moiety appeared to be the most optimal for decreasing cannabinoid receptor affinity without impacting Cav3.2 calcium channel block.
A first series consists of bicyclic macrolactones, where the carboxy terminus of the natural compound was substituted by peptidomimetic aminomethylphenylacetic acid derivatives.
Several other compounds (compounds B1 B9) in this series exhibited higher pancreatic lipase inhibitory activities than that of compound A1, which was the best inhibitor of the first series.
We observed the confirmed hits can be classified into two distinct chemical series: compounds A D, consisting of one series, and compound E, representing second series.
The second series of bioactive compounds are congeners of allocolchicine (3).
