Preliminary insights into associations between C-reactive protein and social network dynamics.

Recent social psychoneuroimmunology models suggest bidirectional associations between social experiences and the immune system. This work posits that social relationships and networks may influence the functioning of the immune system, but we know little about the role that the immune system plays in how social networks are created and maintained. We examine how salivary C-reactive protein (CRP), as an inflammatory protein, is associated with making new and keeping existing friendship and conflicted relationships among young adult members of a social group. Participants (n = 37; 67.6% female; M age = 18.18 years, 56.81% white/non-Hispanic) provided nominations of friends and individuals with whom they have conflict at wave 1 and two months later at wave 2. At wave 1, in a group setting, participants donated saliva, later assayed for CRP. Stochastic actor-based models revealed that CRP levels were negatively associated with keeping existing friends and positively associated with developing new friendships. We also found that CRP levels were negatively associated with creating new conflicted relationships and predicted an increased likelihood that group members continue conflicted relationships with the focal individual. These preliminary results support the premises of recent social psychoneuroimmunology models by suggesting that inflammation can also serve as a signal to seek new supportive relationships such as friendships and avoid creating new relationships characterized by threat and/or conflict. Findings provide new insights into the theorized function of the immune system for social approach and withdrawal patterns through which our social connections are constructed.

On the structure of palau'amine: evidence for the revised relative configuration from chemical synthesis.

Hexacyclic congeners 3 and 4 of palau'amine, which incorporate both guanidine functional groups and have the cis configuration of the azabicyclo[3.3.0]octane core, are prepared in 14 steps from cycloadduct 6. Synthetic access to these analogues allows the first direct comparison of NMR data for hexacyclic diguanidine structures having the originally proposed cis-azabicyclo[3.3.0]octane fragment with data for natural alkaloids of the palau'amine family. This comparison provides convincing evidence in favor of the recently proposed structural revision of these marine alkaloids, fully supporting the trans configuration of the central azabicyclo[3.3.0]octane ring system of palau'amine and congeners.

Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity.

A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.

Catalytic asymmetric synthesis of allylic aryl ethers.

[reaction: see text] The reaction of trichloroacetimidate derivatives of (Z)-2-alken-1-ols with phenol nucleophiles in the presence of the palladium(II) catalyst [COP-OAc]2 provides 3-aryloxy-1-alkenes in high yields and high enantiomeric purity (typically 63-90% yield and 90-97% ee). The reaction is exemplified by 20 examples. The method employs 1 mol % of the commercially available catalysts (S)- or (R)-[COPOAc]2, produces the branched isomer with unprecedented regioselectivity, and is compatible with the presence of base-labile functionality in either reactant.

Propionylpiperazines as human melanocortin-4 receptor ligands.

A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.

Arylpropionylpiperazines as antagonists of the human melanocortin-4 receptor.

A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.

Practical asymmetric synthesis of alpha-branched 2-piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines.

[reaction: see text] 2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.

Structure-activity relationship studies on a series of cyclohexylpiperazines bearing a phanylacetamide as ligands of the human melanocortin-4 receptor.

Synthesis and structure-activity relationship studies of a series of cyclohexylpiperazines bearing an amide side chain as ligands of the MC4 receptor are discussed. Compounds such as 11i from this series are potent agonists (EC(50)=33nM, IA=96%).

Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines.

The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.

Identification of agonists and antagonists of the human melanocortin-4 receptor from piperazinebenzylamines.

SAR studies of a series of piperazinebenzylamines resulted in identification of potent agonists and antagonists of the human melanocortin-4 receptor. Thus, the 1,2,3,4-tetrahydroisoquinolin-1-ylacetyl compound 12e and the quinolin-3-ylcarbonyl analogue 12l possessed K(i) values of 6.3 and 4.5 nM, respectively. Interestingly, 12e was a full agonist with an EC(50) value of 31 nM, and 12l was a weak partial agonist (IA=17%) and functioned as an antagonist (IC(50)=300 nM).

Structure-activity relationships of piperazinebenzylamines as potent and selective agonists of the human melanocortin-4 receptor.

SAR studies on a series of piperazinebenzenes directed toward the human melanocortin-4 receptor resulted in potent MC4R agonists. Replacement of the triazole moiety of an initial lead 4 by a basic nitrogen baring a lipophilic side-chain increased the binding affinities of these compounds. Analogs bearing an additional hetero-atom in the side-chain possessed good agonist potency. Thus, 11h had a Ki of 11 nM, and 13g exhibited an EC50 of 3.8 nM and a Ki of 6.4 nM.