5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1) receptor antagonists: structural modifications at the tryptophan domain

Analogues of the previously reported potent and highly selective CCK(1) receptor antagonist (4aS, 5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido-[1, 2-c]pyrimidine (2a) were prepared to explore the structural requirements at the Boc-tryptophan domain for CCK(1) receptor affinity. Structural modifications of 2a involved the Trp side chain, its conformational freedom, the Boc group, and the carboxamide bond. Results of the CCK binding and in vitro functional activity evaluation showed three highly strict structural requirements: the type and orientation of the Trp side chain, the H-bonding acceptor carbonyl group of the carboxamide bond, and the presence of the Trp amino protection Boc. Replacement of this acid-labile group with 3, 3-dimethylbutyryl or tert-butylaminocarbonyl conferred acid stability to analogues 14a and 15a, which retained a high potency and selectivity in binding to CCK(1) receptors, as well as an in vivo antagonist activity against the acute pancreatitis induced by caerulein in rats. Oral administration of compounds 14a and 15a also produced a lasting antagonism to the hypomotility induced by CCK-8 in mice, suggesting a good bioavailability and metabolic stability.     

The potential contributions of chronic inflammation to lung carcinogenesis

A number of lines of evidence suggests that chronic inflammation contributes to the process of carcinogenesis. In this article, this theme is explored with particular emphasis on the involvement of inflammation in the development of lung cancer. A number of molecular pathways activated in chronic inflammation may contribute to lung carcinogenesis. The challenge is to conceptualize a cohesive picture of this complex biology that allows for effective pharmaceutical intervention. Initial therapeutic efforts involve strategies to block single pathways, such as with cyclooxygenase (COX) activity. However, the more that is learned about the consequences of COX activity, the more evident are the relationships of this enzyme to other classes of regulatory molecules such as the potent nuclear factor-kB. In light of this emerging picture, more global intervention strategies, such as with drug combinations, may be essential for success. Further basic study is essential to sort out possible molecular relationships and to permit elucidation of the most critical regulatory circuits. Given the complexity of these molecular interactions, well-designed clinical trials that specifically evaluate the precise effects of particular antiinflammatory drugs on lung carcinogenesis will also be critical to sort out the complexity and to validate successful approaches to arresting lung carcinogenesis.     

Accelerated phase of idiopathic pulmonary fibrosis

The natural history of idiopathic pulmonary fibrosis is characterized by a slow progression resulting in respiratory failure and death. The progression to the fulminant form is rapid in a small percentage of cases, however. Within weeks or months, patients develop respiratory distress, and extensive ground-glass patterns can be seen in computed tomography scans and hyaline membranes in biopsy samples. This is described as an accelerated phase of idiopathic pulmonary fibrosis, in which elevated levels of acute-phase reactants and tumor markers have been reported. To date, the monoclonal tumor marker, CA 15/3 has not been associated with the accelerated phase.     

Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism

Background

Echocardiography remains a clinically useful screening test for chronic thromboembolic pulmonary hypertension (CTEPH) in patients with a history of pulmonary embolism (PE). To devise an effective screening strategy, the definition of a high-risk group is necessary.

Methods

We examined a total of 744 patients with acute symptomatic pulmonary embolism (PE) who were enrolled in a Spanish multicenter study. Patients were monitored every 6 months during the first two years, and then once a year thereafter. Transthoracic echocardiography was used to screen patients with a clinical suspicion of CTEPH during follow-up. Pulmonary arterial hypertension was defined as an estimated pulmonary artery systolic pressure (PAP) > 50 mm Hg. The index thromboembolic episode was considered severe if: (a) the patient was immobilized for medical reasons; or (b) systolic blood pressure was less than 90 mm Hg; or (c) troponin T values were above the reference range.

Results

The incidence of PAP > 50 mm Hg at 36 months was 8.3% (95% confidence interval = 4.6%-14.5%). Statistical analysis showed a highly significant association between a severe index thromboembolic episode and the subsequent detection of PAP > 50 mm Hg on echocardiography, with high positive likelihood ratio (2.40) and negative predictive value (> 0.97).

Conclusions

Patients with a severe index thromboembolic episode would constitute a high-risk group for the development of CTEPH. This group of patients should be subjected to a strict follow-up protocol.     

Peripheral vascular changes after home-based passive leg cycle exercise training in people with paraplegia: a pilot study

Ballaz L, Fusco N, Crétual A, Langella B, Brissot R. Peripheral vascular changes after home-based passive leg cycle exercise training in people with paraplegia: a pilot study.

Objective

To determine the hemodynamic adaptations after home-based passive leg cycle exercise training in person with paraplegia.

Design

A randomized controlled trial (small cohort).

Setting

University department of physical medicine and rehabilitation.

Participants

A volunteer sample of people with paraplegia (N=17).

Intervention

Subjects within the experimental group performed 36 passive cycling sessions at home.

Main Outcome Measures

Before and after training, we measured heart rate and maximal and minimal femoral artery blood flow velocity at rest and immediately after a 10-minute session of passive cycling by using a quantitative duplex Doppler ultrasound. For each condition, we calculated the mean blood flow velocity and velocity index (VI), used as an indicator of peripheral resistance.

Results

At rest, after training, mean blood flow velocity (P=.08) and VI did not differ significantly in the experimental group compared with the pretraining values (nonparametric analysis). However, in this group, the postexercise mean blood flow velocity and VI are respectively increased and decreased after training (P<.05) compared with the pretraining values. No changes were noted in the control group.

Conclusions

Six weeks of home-based passive cycling training have no significant effect on the rest hemodynamic values but increase the hemodynamic response to acute passive cycling exercise.     

Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors

It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH-DPAT-stimulated GTPgammaS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.     

Acute peripheral blood flow response induced by passive leg cycle exercise in people with spinal cord injury

OBJECTIVE: To determine the acute femoral artery hemodynamic response in paraplegic subjects during a passive leg cycle exercise. DESIGN: Case series. SETTING: Department of physical medicine and rehabilitation in a university in France. PARTICIPANTS: A volunteer sample of 15 people with traumatic spinal cord injury. INTERVENTION: Subjects performed a 10-minute session of passive leg cycle exercise in the sitting position. MAIN OUTCOME MEASURES: We measured heart rate, maximal (Vmax), and minimal femoral artery blood flow velocity at rest and immediately after the passive leg cycle exercise, using quantitative duplex Doppler ultrasound. We calculated mean blood flow velocity (Vmean) and velocity index, representing the peripheral resistance, for each condition. RESULTS: Vmax and Vmean increased (from .80+/-.18 m/s to .96+/-.24 m/s, P<.01; and from .058+/-.02 m/s to .076+/-.03 m/s, P<.01; respectively) after 10 minutes of passive leg cycle exercise. Heart rate did not change. The velocity index decreased from 1.23+/-0.15 to 1.16+/-0.21 (P=.038). CONCLUSIONS: The results of this study suggest that acute passive leg cycle exercise increases vascular blood flow velocity in paralyzed legs of people with paraplegia. This exercise could have clinical implications for immobilized persons.