Cortistatin

Human cortistatin-17 Binding to sst2 5 with high affinity, slightly lower preference for sst-,... 

Rat cortistatin-29 Binding to sst3 with high affinity, slightly lower preference for sst-, sst4 and sst2, and lower preference for sst5 (i.e. 100-fold lower than that of somatostatin-14)... 

Cortistatin a cortical neuropeptide with sleep-modulating activity... 

Cortistatin was discovered as a result of the effort to characterize cortex-specific gene expression modulated by synaptic activity. It was named after its cortical expression and sequence homology to somatostatin (de Lecea et a ., 1996). The characterization of this peptide is yet another example of the use of reverse genetics to study the molecular components of the sleep machinery. 

Cortistatin is synthesized as a precursor of 116 amino acids that gives rise to a C-terminal mature peptide, cortistatin-14 (CST-14), that shares 11 of its 14 residues with the neuropeptide somatostatin. However, the similarities between cortistatin and somatostatin are restricted to the mature peptides, which are the products of different genes. CST-14 binds to all five somatostatin receptors in vitro, although several authors suggest that CST-14 exerts its actions in vivo by binding to its own specific receptor (Spier de Lecea, 2000). 

Intracerebroventricular infusion of CST-14 dramatically increases the amount of slow wave activity in rats, at the expense of wakefulness. The mechanism by which CST-14 enhances cortical synchronization has been established through the interaction of CST-14 with acetylcholine, a neurotransmitter known to be involved in the maintenance of cortical desynchronization. Application of acetylcholine (ACh) in the anesthetized animal increases fast activity, and this effect is blocked with the simultaneous addition of CST-14. These data suggest that CST-14 increases slow wave sleep by antagonizing the effects of ACh on cortical excitability. In addition to this mechanism, cortistatin may enhance cortical... 

Several studies suggest that cortistatin expression correlates with the sleep homeostat. The concentration of cortistatin mRNA oscillates with the light-dark cycle in rats, with maximal levels at the end of the dark (i.e. active) period. Further, the steady-state concentration of cortistatin mRNA increases four-fold after sleep deprivation, and returns to normal levels after sleep rebound, indicating that the expression of the peptide is associated with sleep demand (Spier de Lecea, 2000). Preliminary studies in cortical slices suggest that cortistatin-14 increases cortical synchronization by enhancing the H-current. Thus, cortistatin and somatostatin may be part of the intrinsic mechanisms of the cerebral cortex that are involved in the maintenance of excitability. 

Spier AD, De Lecea L. Cortistatin amemberof the somatostatin neuropeptide family with distinct physiological functions. Brain Res Rev 2000 33 228-241. 

Cortistatins A-D (10-13) were isolated from the marine sponge Corticium simplex [13]. These steroidal alkaloids are unrelated to cortistatin, a neuropeptide stmcturally related to the hormone somatostatin which has antiangiogenic activity [14]. 

Interpretation of 2 D NM R data obtained for cortistatin B (11) showed that it had the same skeleton as 10, but contained a hydroxyl group on C-16 with the (3 configuration. The carbon chemical shift value of 8 214.4 and the IR absorption at 1740 cm indicated the existence ofa ketone at C-16 in cortistatin C (12). Cortistatin D (13) was found to be a 17-hydroxy analog of cortistatin C, which was confirmed by "C NMR deuterium shift experiments as well as HMBC data. Analysis of NOESY data for 13 revealed the orientation of hydroxyl group at C-17 as a [13]. 

Cortistatin A exhibited antiproliferative activity against H UVECs at low nano molar concentrations [13[. This potent activity appeared highly selective since the proliferation of four cancer cell lines was inhibited only at 3000-fold higher concentrations. Cortistatin C inhibited HUVEC proliferation 10-fold less potently than cortistatin A but it retained the remarkable selectivity of 10. Cortistatins B and D were less potent still, but nevertheless exhibited good selectivity toward HUVECs. Cortistatin A was also shown to prevent bFGF- and VEGF-induced HUVEC migration and tube formation at low nanomolar concentrations [13]. 

Cortistatin exhibits strong structural similarity to SST (Fig. 1), although it is the product of a different gene. By in situ hybridization cortistatin mRNA was detected in the cortex and hippocampus, where SST is also present, but not in the hypothalamus and some peripheral tissues where SST is abundant. Administration of cortistatin depresses neuronal electrical activity but, unlike SST, induces low-frequency waves in the cerebral cortex and antagonizes the effects of acetylcholine on hippocam-... 

Fig. 1. Alignment of the amino acid sequences of rat somatostatin-28 with those deduced from rat and human cortistatin cDNA predicted to form 29 amino acid peptides. Note that the conserved parts are located in the ring constituent (indicated by square brackets) and the extension of the ring structure by one amino acid in cortistatin. Also within the ring cortistatin displays the Trp-Lys motif that is essential for receptor binding (see Sect. 4)...

Fukusumi S, Kitada C, Takekawa S, Sakamoto J, Miyamoto M, Hinuma S, Kitano K, Fujino M (1997) Identification and characterization of a novel human cortistatin-like peptide. Biochem Biophys Res Commun 232 157-163... 

Cycloadditions of nitrones with the triple bond are also valuable and give isoxazoline derivatives. An advanced use of this cycloaddition is reported in a paper directed to the synthesis of a portion of the stmcture of the natural product cortistatin. Here, the triple bond is generated in the form of a benzyne (5.30, Scheme 5.32 A) in the presence of a nitrone. Benzynes, of course, are not stable at room temperature and must be generated as needed in a reaction mixture. In this particular case, the nitrone reactant had this group conjugated to a double bond, as shown in stmcture 531. The cycloaddition proceeded normally to give the adduct 5.32. 

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