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  • br Biologically active non peptide galanin receptor ligands


    Biologically active non-peptide galanin receptor ligands The first successful attempt in overcoming these weaknesses was undertaken by Saar et al. (2002). Screening of galanin sequence established that Trp-2, Asn-5, Tyr-9 were pharmacophores, responsible for biochemical action of the peptide. Based on this finding, and by applying combinatorial approach, Saar et al. (2002) synthesized the first non-peptide low molecular weight GalR agonist galnon (Fmoc-Cha-Lys-amidomethylcoumarin, Fig. 7(a)), which penetrated thorough blood–brain barrier. Galnon showed potent anticonvulsant effects pentylenetetrazole seizures upon systemic administration, as well as inhibited perforant path stimulation-induced SE in rats (Saar et al., 2002). Anticonvulsant effects of galnon were attenuated, although not abolished, in the animals which had been pretreated by PNA targeted at GalR1, thus implicating this GalR subtype in mediating at least in part, the anticonvulsant effects of galnon. Recently, another non-peptide GalR agonist, galmic (Fig. 7(b)) has been synthesized (Bartfai et al., 2004). While galnon has a flexible backbone that can assume many shapes and the side chains can attain numerous orientations and distances from one another, galmic has an inner core structure that is rigid and roughly planar. The three side chains protruding from the large ring are always on the same face of the structure and their distances from one another are fixed. On other words, galmic is a conformationally restrained version of galnon, just as an alpha helix is a conformationally restrained version of a random coil. In contrast to galnon which did not discriminate between GalR subtypes, galmic preferred GalR1 over GalR2. This compound was also effective in inhibiting seizures induced by both perforant path stimulation (Bartfai et al., 2004) and pentylenetetrazole (personal unpublished data) upon systemic administration.
    Conclusions The interest in neuropeptides as modulators of seizure activity is not surprising. Indeed, neuropeptides are powerful and versatile modulators of classical neurotransmitters and are present in d cycloserine areas which are intimately involved in epileptogenesis. The properties of neuropeptides make them appealing targets for both studying basic mechanisms of seizure initiation and arrest, and for the development of novel approaches for epilepsy treatment (Hokfelt and Bartfai, 2003, Wasterlain et al., 2002). Evidently, while many of neuropeptides share fundamental mechanisms which underlie their anticonvulsant action, the specifics of their neuroanatomical localization and biochemical properties define the unique role for each of the neuropeptide in inhibiting or promoting seizures (Baraban and Tallent, 2004, Wasterlain et al., 2002).
    Introduction Puberty is the developmental period during which an immature juvenile acquires the capacity to reproduce for the first time. The activation of the hypothalamus–pituitary–gonadal (HPG) axis is a key event at the onset of puberty: gonadotropin-releasing hormone (GnRH) secreted by hypothalamic neurons stimulate the pituitary secretion of gonadotropins, that stimulate the production of sex steroids and support gametogenesis in the gonads (Colledge, 2004, Taranger et al., 2010). However, before the full activation of the pulsatile GnRH secretion a series of neuroendocrine events need to occur, which appears to integrate genetic, internal and environmental signals that influence the timing of puberty (Taranger et al., 2010). Kisspeptins and their receptor GPR54 appear to be important in integrating these signals in the brain at puberty onset (Colledge, 2004, Felip et al., 2009), but additional triggers of pubertal GnRH activation are also thought to be involved. A likely candidate integrator of different signals to trigger puberty onset is galanin (GAL). GAL is a neuropeptide that mediates multiple physiological processes in vertebrates, including learning, nociception, food intake and reproduction (Lang et al., 2007). GAL is mainly localized in the brain and pituitary gland and GAL immunoreactive (GAL-ir) fibers projecting from the hypothalamic region onto the pituitary are well characterized in fish (Cornbrooks and Parsons, 1991a, Cornbrooks and Parsons, 1991b, Moons et al., 1991, Olivereau and Olivereau, 1991, Anglade et al., 1994, Power et al., 1996) and mammals (Ch’ng et al., 1985, Arai et al., 1990, Gai et al., 1990). In the pituitary, GAL is mainly detected in the pars distalis, in close contact with somatotropes, and has been shown to affect growth hormone and prolactin secretion (Bauer et al., 1986, Diez et al., 1992, Wynick, 1998).