Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist.

Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.

Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Caregiving and developmental factors differentiating young at-risk urban children showing resilient versus stress-affected outcomes: a replication and extension.

This study tested hypotheses from an organizational-developmental model for childhood resilience. In this model resilience reflects a child's mastery of age-salient objectives, in the face of substantial adversity, by drawing on internal and external resources that enhance processes of adaptation specific to each developmental stage. Interviews were conducted with parents of 122 7- to 9-year-old urban children exposed to multiple risk factors, 69 classified as resilient and 53 as maladjusted. Consistent with predictions generated by the model: (1) characteristics of a child's caregiving system and early development differentiated children with resilient and stress-affected adaptations; and (2) variables reflecting emotionally responsive, competent parenting were direct, proximal predictors of resilient status and mediators of other caregiver resources such as education, mental health, and relational history. Identified predictors of resilient status, including competent parenting and caregiver psychosocial resources, largely replicated findings from a prior study with sociodemographically comparable 9- to 12-year-old children.

Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.

The selective 5-HT1B receptor inverse agonist 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo.

5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

Follow-up study of young stress-affected and stress-resilient urban children.

Reports follow-up study of 181 young highly stressed urban children, classified as stress-resilient (SR) and stress-affected (SA) 1 1/2-2 years earlier. At follow-up (T2), children were retested on five initial (T1) test measures: self-rated adjustment, perceived competence, social problem solving, realistic control attributions, and empathy; parents and teachers did new child adjustment ratings, and parents participated in a phone interview focusing on the T1-T2 interval. Child test and adjustment measures and parent interview responses at T2 sensitively differentiated children classified as SR and SA at T1. Test and interview variables used at T1 and T2 correlated moderately across time periods. At T2, four child test indicators (i.e., rule conformity, global self-worth, social problem solving, and realistic control attributions) and four parent interview variables (positive future expectations for the child, absence of predelinquency indicators, good parent mental health in the past year, and adaptive parent coping strategies) sensitively differentiated children classified as SR and SA at T1. No relationship was found between family stress experienced in the T1-T2 interval and changes in children's adjustment during that period.

Azabicyclic indole esters as potent 5-HT4 receptor antagonists.

The synthesis of a series of azabicyclic indole esters is described and their potency reported as 5-HT4 receptor antagonists. Optimization of the most potent compound (19) by preparing the corresponding oxazino[3,2-a]indole ester afforded 34, which had a pIC50 of 9.5 in the guinea pig distal colon longitudinal muscle myenteric plexus preparation.

Resilience in highly stressed urban children: concepts and findings.

The Rochester Child Resilience Project is a coordinated set of studies of the correlates and antecedents of outcomes relating to resilience among profoundly stressed urban children. The studies have been conducted over the course of the past decade. Based on child test data, parent, teacher, and self ratings of child adjustment, and in-depth individual interviews with parents and children, a cohesive picture has developed of child and family milieu variables that consistently differentiate children with resilient versus stress-affected outcomes within this highly stressed sample. Resilient children are characterized by an easy temperament and higher IQ; sound parent/child relationships; a parent's sense of efficacy; the parent's own wellness, especially mental health; and the child's perceived competence, realistic control, empathy, and social problem-solving.

A preventive intervention for enhancing resilience among highly stressed urban children.

Describes the development and evaluation of a pilot 12-session, school-based preventive intervention designed to enhance resilience among inner-city children who have experienced major life stress. Thirty-six 4th-6th grade children participated in the intervention in groups of 5-8 co-led by school personnel. The curriculum focussed on understanding feelings in oneself and others, perspective-taking, social problem-solving, dealing with solvable and unsolvable problems, and building self-efficacy and esteem. Pre-post evaluation showed significant improvement among participants on teacher-rated indices of learning problems and task orientation and on child ratings of perceived self-efficacy, realistic control attributions and anxiety. Program limitations and factors that restrict generalization are considered and new directions for program development and research are proposed.

Relationships between retrospective parent reports of developmental milestones and school adjustment at ages 10 to 12 years.

OBJECTIVE: The study's main purpose was to assess the extent to which retrospective parent reports of the child's achievement of early developmental milestones predicted later (fourth to sixth grade) adaptation to stress, and school adjustment and achievement, in a highly stressed urban sample. METHOD: Information about when children achieved key developmental milestones was obtained in individual parent interviews. Information about the child's current school adjustment and achievement was obtained from classroom teachers and school records. RESULTS: Factor analysis of a 12-item developmental milestone measure yielded an interpretable two-factor solution, i.e., motor and verbal milestones. Parents of stress-resilient, compared with stress-affected, children reported significantly earlier developmental milestone mastery by their offspring on both factor and total scores. Developmental factor milestone and total scores also related modestly to indicators of good school adjustment and academic achievement at ages 10 to 12 years. CONCLUSION: Delayed mastery of early developmental milestones may be a risk factor toward which preventive interventions can be gainfully targeted.

Parent and child views of parent-child relationship qualities and resilient outcomes among urban children.

Separate in-depth interviews were conducted with two groups of highly stressed 4th-6th grade urban children classified as stress-affected (SA) and stress-resilient (SR), and their parents. Judges identified interview items reflecting three components of a good parent-child relationship, i.e. positive parental attitudes, involvement and guidance. SR parents and children scored higher than their SA counterparts on all three relational dimensions. Additionally, SR parent-child dyads had more congruent views of their relationship than SA dyads. These findings suggest that positive parent-child relationship qualities play an important protective role that favors resilient outcomes, at ages 10-12, among children who have experienced major life stress.

Interviews with children who experienced major life stress: family and child attributes that predict resilient outcomes.

Demographically comparable groups of children exposed to major life-stress, with stress resilient (SR) and stress affected (SA) outcomes at ages 10 to 12, were interviewed to assess perceptions of their caregiving environments, peer relationships, and themselves. SR children compared with SA children reported more: (1) positive relationships with primary caregivers, (2) stable family environments, (3) inductive and consistent family discipline practices, and (4) positive expectations for their futures. SR girls viewed their mothers as more nurturing than did SA girls. Perceptions of fathers, quality of peer relationships, and global self-concept did not differentiate the groups. A discriminant function analysis identified four variables that correctly classified 74% of the subjects as SR or SA. Findings support the view that caregiver-child relationships play a key role in moderating children's developmental outcomes under conditions of high stress.

Substituent variation in azabicyclic triazole- and tetrazole-based muscarinic receptor ligands.

The effect of variation of the 1-azabicyclic substituent on the novel 1,2,3-triazol-4-yl-, 1,2,4-triazol-1-yl, tetrazol-5-yl-, and tetrazol-2-yl-based muscarinic receptor ligands has been studied, and the exo-azabicyclic[2.2.1]hept-3-yl substituent was found to give the most potent and efficacious compounds. In addition, variation of the second substituent on 1,2,4-triazol-1-yl- and tetrazol-2-yl-based muscarinic receptor ligands has yielded a series of novel compounds with high potencies and efficacies, ranging from full agonists to antagonists. Small lipophilic electron withdrawing substituents give potent but low efficacy compounds, while small polar electron donating substituents give potent and efficacious compounds. The activity of these compounds is described in terms of a model of the receptor involving lipophilic and hydrogen bonding interactions. These compounds provide muscarinic ligands with high potency and a range of efficacies suitable for testing as candidate drugs in the treatment of Alzheimer's disease.

The relationship between retrospective reports of early child temperament and adjustment at ages 10-12.

For 131 highly stressed 4th- to 6th-grade urban children, retrospective parental reports of child temperament along an easy-difficult dimension, for the infancy (ages 0-2) and preschool (ages 2-5) periods, were obtained during in-depth interviews. Parent judgments of an easier temperament in each of the two age periods, and their sum, related consistently and significantly to positive ratings of current child adjustment. The latter reflected both multiple sources (i.e., parents, former teachers, and current teachers) and different aspects of adjustment (e.g., fewer problem behaviors and more competencies).

Similarity of parent and child self-views in stress-affected and stress-resilient urban families.

This study was conducted with a sample of highly stressed 4th-6th grade urban children consisting of matched subsamples previously classified as stress affected (SA) or stress resilient (SR). Separate in-depth interviews with parents and children provided objective self-ratings of a number of personal characteristics and expressive motor behavioral styles. Based on subsets of identical items from the two interviews, discrepancy (D)-scores were computed between parents' and children's self-ratings of ten personal descriptors, seven expressive motor behaviors, and their sum. Significantly lower D-scores were found for SR, compared to SA, parent-child dyads on all three of these measures. For the total sample, small parent-child D-scores also related significantly to indicators of fewer child problem behaviors and more competencies, assessed across multiple rater sources (i.e., parents, former teachers, and current teachers).

Developmental and family milieu correlates of resilience in urban children who have experienced major life stress.

Reports findings from interviews with parents of demographically-comparable groups of highly-stressed urban children with stress-resilient (SR) and stress-affected (SA) outcomes at ages 10-12. SR and SA children were compared on family milieu and child development variables assessed within a developmental framework. Compared to SAs, parents of SRs scored higher on variables reflecting parent perceptions of a nurturant caregiver-child relationship and self-views as effective caregivers, in the context of positive discipline practices, a child's positive early temperament, and support for primary caregivers. A discriminant function analysis identified seven variables that optimally differentiated the groups and correctly classified 86% of the Ss as SR or SA.

Stress resilient children in an urban setting.

Overviews the Rochester Child Resilience Project, describes its design and measures, and presents preliminary findings. Within a sample of 313 urban 4th-6th graders, convergent sources of evidence identified subsamples of 37 stress affected (SA) and 40 stress resilient (SR) children, all of whom, based on parent report, had experienced ≥4 stressful life events and circumstances (SLE-Cs). The combined SR/SA groups averaged 8.9 SLE-Cs, significantly more than the rest of the sample. Detailed adjustment ratings by current classroom teachers confirmed that SRs were significantly better adjusted than both SAs and a demographically matched low-stress sample. Factor analysis of the stressful events checklist identified 5 factors. Pooled SRs and SAs had higher scores on these factors than the rest of the sample. In direct comparison of the two groups, SAs had higher scores than SRs only on the Family Separation factor.