Mission impossible? Spatial context relearning following a target relocation event depends on cue predictiveness.

Visual search for a target is faster when the spatial layout of distractors is repeatedly encountered, illustrating that statistical learning of contextual invariances facilitates attentional guidance (contextual cueing; Chun & Jiang, 1998, Cognitive Psychology, 36, 28-71). While contextual learning is usually relatively efficient, relocating the target to an unexpected location (within an otherwise unchanged search layout) typically abolishes contextual cueing and the benefits deriving from invariant contexts recover only slowly with extensive training (Zellin et al., 2014, Psychonomic Bulletin & Review, 21(4), 1073-1079). However, a recent study by Peterson et al. (2022, Attention, Perception, & Psychophysics, 84(2), 474-489) in fact reported rather strong adaptation of spatial contextual memories following target position changes, thus contrasting with prior work. Peterson et al. argued that previous studies may have been underpowered to detect a reliable recovery of contextual cueing after the change. However, their experiments also used a specific display design that frequently presented the targets at the same locations, which might reduce the predictability of the contextual cues thereby facilitating its flexible relearning (irrespective of statistical power). The current study was a (high-powered) replication of Peterson et al., taking into account both statistical power and target overlap in context-memory adaptation. We found reliable contextual cueing for the initial target location irrespective of whether the targets shared their location across multiple displays, or not. However, contextual adaptation following a target relocation event occurred only when target locations were shared. This suggests that cue predictability modulates contextual adaptation, over and above a possible (yet negligible) influence of statistical power.

Why Are Acquired Search-Guiding Context Memories Resistant to Updating?

Looking for goal-relevant objects in our various environments is one of the most ubiquitous tasks the human visual system has to accomplish (Wolfe, 1998). Visual search is guided by a number of separable selective-attention mechanisms that can be categorized as bottom-up driven - guidance by salient physical properties of the current stimuli - or top-down controlled - guidance by observers' "online" knowledge of search-critical object properties (e.g., Liesefeld and Müller, 2019). In addition, observers' expectations based on past experience also play also a significant role in goal-directed visual selection. Because sensory environments are typically stable, it is beneficial for the visual system to extract and learn the environmental regularities that are predictive of (the location of) the target stimulus. This perspective article is concerned with one of these predictive mechanisms: statistical context learning of consistent spatial patterns of target and distractor items in visual search. We review recent studies on context learning and its adaptability to incorporate consistent changes, with the aim to provide new directions to the study of processes involved in the acquisition of search-guiding context memories and their adaptation to consistent contextual changes - from a three-pronged, psychological, computational, and neurobiological perspective.

Design and synthesis of novel potent and selective integrin alphanubeta3 antagonists--novel synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates.

An unexpected ring contraction of benzazepinone based alpha(nu)beta(3) antagonists led to the design of quinolinone-type derivatives. Novel and efficient synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates were established. Nanomolar alpha(nu)beta(3) antagonists based on these new scaffolds were prepared. Moreover, benzoxazinones 15a and 15b exhibited high microsomal stability and good permeability.

Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety.

The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.

Orally active thrombin inhibitors. Part 2: optimization of the P2-moiety.

Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.

D-Phe-Pro-Arg type thrombin inhibitors: unexpected selectivity by modification of the P1 moiety.

Synthesis of thrombin inhibitors and their binding mode to thrombin is described. Modification of the P1 moiety leads to an increased selectivity versus trypsin. The observed selectivity is discussed in view of their thrombin-inhibitor complex X-ray structures.

Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin alphaVbeta3 antagonists.

The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel alpha(V)beta(3) inhibitors displaying potency in the subnanomolar range, selectivity versus alpha(IIb)beta(3) and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.

Highly potent and selective alphaVbeta3-receptor antagonists: solid-phase synthesis and SAR of 1-substituted 4-amino-1H-pyrimidin-2-ones.

Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to subnanomolar range and high selectivity versus related integrins like alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays was demonstrated.

Synthesis and SAR of N-substituted dibenzazepinone derivatives as novel potent and selective alpha(V)beta(3) antagonists.

Synthesis and SARs of new integrin alpha(V)beta(3) antagonists based on an N-substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC(50) towards alpha(V)beta(3) in the nanomolar range, high selectivity versus integrin alpha(IIb)beta(3) and efficacy in functional cellular assays.