Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

Evaluation of α-hydroxycinnamic Acids as Pyruvate Carboxylase Inhibitors

Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3′-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase

Argument evaluation and production in the correction of political innumeracy

International audienceThe public is largely innumerate, making systematic mistakes in estimating some politically relevant facts, such as the share of foreign-born citizens. In two-step or multistep flow models, such mistakes could be corrected if better-informed citizens were able to convince their peers, in particular by using good arguments citing reliable sources. In six experiments, we find two issues that dampen the potential power of this two-step flow process. First, even though participants were more convinced by good than by poor arguments, many did not change their minds, even when confronted with good arguments. Second, participants are not inclined to spontaneously generate arguments that cite reliable sources, even when they have just been influenced by such arguments. Both issues should put a significant brake in the spread of political numeracy through the two-step flow process, in particular in non-dialogic contexts

Understanding distal goals from proximal communicative actions

Can people interpret communicative action modulations in terms of the actor’s distal goal? We investigated situations in which the proximal goal of an action (i.e., the movement endpoint) does not overlap with its distal goal (i.e., a final location beyond the movement endpoint). Participants were presented with animations of an object being moved at different velocities towards a designated endpoint. The distal goal, however, was for the object to be moved past this endpoint, to one of two occluded final locations. Participants were asked to select the location which they considered the likely distal goal of the action. As predicted, participants detected differences in movement velocity and, based on these differences, systematically mapped the movements to the two distal goal locations. These findings extend previous research on sensorimotor communication by demonstrating that communicative action modulations are not restricted to proximal goals but can also contain information about distal goals

Understanding others’ distal goals from proximal communicative actions

Many social interactions require individuals to coordinate their actions and to inform each other about their goals. Often these goals concern an immediate (i.e., proximal) action, as when people give each other a brief handshake, but they sometimes also refer to a future (i.e. distal) action, as when football players perform a passing sequence. The present study investigates whether observers can derive information about such distal goals by relying on kinematic modulations of an actor’s instrumental actions. In Experiment 1 participants were presented with animations of a box being moved at different velocities towards an apparent endpoint. The distal goal, however, was for the object to be moved past this endpoint, to one of two occluded target locations. Participants then selected the location which they considered the likely distal goal of the action. As predicted, participants were able to detect differences in movement velocity and, based on these differences, systematically mapped the movements to the two distal goal locations. Adding a distal goal led to more variation in the way participants mapped the observed movements onto different target locations. The results of Experiments 2 and 3 indicated that this cannot be explained by difficulties in perceptual discrimination. Rather, the increased variability likely reflects differences in interpreting the underlying connection between proximal communicative actions and distal goals. The present findings extend previous research on sensorimotor communication by demonstrating that communicative action modulations are not restricted to predicting proximal goals but can also be used to infer more distal goals

Understanding distal goals from proximal communicative actions

Can people interpret communicative action modulations in terms of the actor’s distal goal? We investigated situations in which the proximal goal of an action (i.e., the movement endpoint) does not overlap with its distal goal (i.e., a final location beyond the movement endpoint). Participants were presented with animations of an object being moved at different velocities towards a designated endpoint. The distal goal, however, was for the object to be moved past this endpoint, to one of two occluded final locations. Participants were asked to select the location which they considered the likely distal goal of the action. As predicted, participants detected differences in movement velocity and, based on these differences, systematically mapped the movements to the two distal goal locations. These findings extend previous research on sensorimotor communication by demonstrating that communicative action modulations are not restricted to proximal goals but can also contain information about distal goals

Understanding distal goals from proximal communicative actions

Can people interpret communicative action modulations in terms of the actor’s distal goal? We investigated situations in which the proximal goal of an action (i.e., the movement endpoint) does not overlap with its distal goal (i.e., a final location beyond the movement endpoint). Participants were presented with animations of an object being moved at different velocities towards a designated endpoint. The distal goal, however, was for the object to be moved past this endpoint, to one of two occluded final locations. Participants were asked to select the location which they considered the likely distal goal of the action. As predicted, participants detected differences in movement velocity and, based on these differences, systematically mapped the movements to the two distal goal locations. These findings extend previous research on sensorimotor communication by demonstrating that communicative action modulations are not restricted to proximal goals but can also contain information about distal goals

Communicative modulations of early action components support the prediction of distal goals.

The successful unfolding of many social interactions relies on our capacity to predict other people's action goals, whether these are proximal (i.e., immediate) or distal (i.e., upcoming). The present set of studies asks whether observers can predict the distal goal of two-step action sequences when presented with communicative modulations of the first movement component of the sequence. We conducted three online experiments in which we presented participants with animations of a box moving to a first target location before moving onwards to a final, either near or far, target location. The second movement component and the target locations were occluded. After observing the first movement, participants were asked to select the most likely final target location, i.e., the distal goal of the sequence. Experiment 1 showed that participants relied on the velocity modulations of the first movement to infer the distal goal. The results of Experiment 2 indicated that such predictions of distal goals are possible even when the second movement in the sequence does not contain any velocity information, thus suggesting that the information present in the first movement plays the major role in the process of linking movements to their distal goals. However, Experiment 3 showed that under some circumstances the second movement can also contribute to how observers predict a distal goal. We discuss these results in terms of the underlying simulation processes that enable observers to predict a distal goal from the observation of proximal communicative modulations