Intellectual and social disabilities are common comorbidities in adolescents and adults with MAGE family member L2 (MAGEL2) gene deficiency characterizing the Prader-Willi and Schaaf-Yang ...neurodevelopmental syndromes. The cellular and molecular mechanisms underlying the risk for autism in these syndromes are not understood. We asked whether vasopressin functions are altered by MAGEL2 deficiency and whether a treatment with vasopressin could alleviate the disabilities of social behavior. We used Magel2-knockout mice (adult males) combined with optogenetic or pharmacological tools to characterize disease modifications in the vasopressinergic brain system and monitor its impact on neurophysiological and behavioral functions. We found that the activation of vasopressin neurons and projections in the lateral septum were inappropriate for performing a social habituation/discrimination task. Mechanistically, the lack of vasopressin impeded the deactivation of somatostatin neurons in the lateral septum, which predicted social discrimination deficits. Correction of vasopressin septal content by administration or optogenetic stimulation of projecting axons suppressed the activity of somatostatin neurons and ameliorated social behavior. This preclinical study identified vasopressin in the lateral septum as a key factor in the pathophysiology of Magel2-related neurodevelopmental syndromes.
It is now accepted that vasopressin, through V1A/V1B receptors, centrally regulates cognitive functions such as memory, affiliation, stress, fear and depression. However, the respective roles of ...these receptor isoforms and their contribution to stress-related pathologies remain uncertain. The development of new therapeutic treatments requires a precise knowledge of the distribution of these receptors within the brain, which has been so far hampered by the lack of selective V1B markers. In the present study, we have determined the pharmacological properties of three new potent rat V1B fluorescent ligands and demonstrated that they constitute valuable tools for simultaneous visualization and activation of native V1B receptors in living rat brain tissue. Thus, dLeu4,Lys-Alexa 647)8VP (analogue 3), the compound with the best affinity-selectivity/fluorescence ratio for the V1B receptor emerged as the most promising. The rat brain regions most concerned by stress such as hippocampus, olfactory bulbs, cortex and amygdala display the highest V1B fluorescent labelling with analogue 3. In the hippocampus CA2, V1B receptors are located on glutamatergic, not GABAergic neurones, and are absent from astrocytes. Using AVP-EGFP rats, we demonstrate the presence of V1B autoreceptors on AVP-secreting neurones not only in the hypothalamus, but also sparsely in the hippocampus. Finally, using both electrophysiology and visualization of ERK phosphorylation, we show analogue 3-induced activation of the V1B receptor in situ. This will help to analyse expression and functionality of V1B receptors in the brain and contribute to further explore the AVPergic circuitry in normal and pathological conditions.
An efficient and facile synthesis of
N-Boc-α-chloromethyl- and α-bromomethyl-α-alkylglycines is reported that involves cyclization of
N-Boc-α-alkylserines to the corresponding β-lactones under ...Mitsunobu reaction conditions, followed by ring opening with anhydrous MgCl
2 or MgBr
2.
It is now accepted that vasopressin, through V
/V
receptors, centrally regulates cognitive functions such as memory, affiliation, stress, fear and depression. However, the respective roles of these ...receptor isoforms and their contribution to stress-related pathologies remain uncertain. The development of new therapeutic treatments requires a precise knowledge of the distribution of these receptors within the brain, which has been so far hampered by the lack of selective V
markers. In the present study, we have determined the pharmacological properties of three new potent rat V
fluorescent ligands and demonstrated that they constitute valuable tools for simultaneous visualization and activation of native V
receptors in living rat brain tissue. Thus, dLeu
,Lys-Alexa 647)
VP (analogue 3), the compound with the best affinity-selectivity/fluorescence ratio for the V
receptor emerged as the most promising. The rat brain regions most concerned by stress such as hippocampus, olfactory bulbs, cortex and amygdala display the highest V
fluorescent labelling with analogue 3. In the hippocampus CA
, V
receptors are located on glutamatergic, not GABAergic neurones, and are absent from astrocytes. Using AVP-EGFP rats, we demonstrate the presence of V
autoreceptors on AVP-secreting neurones not only in the hypothalamus, but also sparsely in the hippocampus. Finally, using both electrophysiology and visualization of ERK phosphorylation, we show analogue 3-induced activation of the V
receptor in situ. This will help to analyse expression and functionality of V
receptors in the brain and contribute to further explore the AVPergic circuitry in normal and pathological conditions.
N-Boc-α-alkylserine β-lactones on ring opening with sodium azide provide
N-Boc-α-alkyl-β-azidoalanines, as N-protected amino acids are suitable for direct incorporation into peptides.
...N-Boc-α-alkyl-β-azidoalanines can be transformed by catalytic hydrogenation into the corresponding
N-Boc-α-alkyl-β-aminoalanines.
The structure of the title compound, C(12)H(21)NO(4), contains two crystallographically independent mol-ecules in the asymmetric unit. Mol-ecules are linked into pseudosymmetric R(2) (2)(8) dimers ...through two N-H⋯O hydrogen bonds. The dimers are connected by weak C-H⋯O inter-actions, resulting in a three-dimensional network.
In this study, proteinogenic amino acids residues of dimeric dermorphin pentapeptides were replaced by the corresponding beta super(3)-homo-amino acids. The potency and selectivity of hybrid alpha / ...beta dimeric dermorphin pentapeptides were evaluated by competetive receptor binding assay in the rat brain using 3HDAMGO (a mu ligand) and 3HDELT (a delta ligand). Tha analog containing beta super(3)-homo-Tyr in place of Tyr (Tyr-d-Ala-Phe-Gly- beta super(3)-homo-Tyr-NH-) sub(2) showed good mu receptor affinity and selectivity (IC sub(50)=0.302, IC sub(50) ratio mu / delta =68) and enzymatic stability in human plasma. In this paper, we describe the synthesis, binding affinity and enzymatic stability of analogs dimeric dermorphin pentapeptides containing beta super(3)-homo-amino acids. Our studies have shown that analogs containing beta super(3)-homo-amino acids exhibit various degree of affinity to mu and delta receptors. Analog I (Tyr-d-Ala-Phe-Gly-Tyr-NH-) sub(2) exhibited good stability to human serum, whilst analog IV (Tyr-d-Ala-Phe-Gly- beta super(3)-homo-Tyr-NH-) sub(2), containing beta super(3)-homo-tyrosine in position 5,5', was found to be extremely stable in human plasma.
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![The impact of [beta]-azido(...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1075-2617/small "The impact of [beta]-azido(or 1-piperidinyl)methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues")