Disease relevance of L-692429

• Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men [1].
• We examined the effects of L-692,429 on cultured human pituitary tumors removed from patients with acromegaly [2].

High impact information on L-692429

• L-692,429 synergizes with the natural growth hormone secretagogue growth hormone-releasing hormone and acts through an alternative signal transduction pathway [3].
• More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template [4].
• L-692,429 also displayed a very similar potency in all signaling assays (25-60 nm) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin's potency 4- to 10-fold [5].
• L-692,429 (L), a novel nonpeptide mimic of GH-releasing peptide (GHRP), is a potent GH secretagogue in animals and young men [6].
• The mean (SE) GH peak and area under the curve between 0-240 min after administration of 0.2 mg/kg L-692,429 in the absence of steroid were 53.8 (7.2) micrograms/L and 3481 (1005) micrograms/min.L, which were reduced to 25.1 (3.4) micrograms/L and 1342 (285) micrograms/min.L (P < or = 0.01) when treatment was preceded by 4 days of prednisolone [7].

Biological context of L-692429

• L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429 [8].
• Thus, the faster clearance of L-692,429 in dogs likely is caused by less extensive plasma protein binding and higher metabolic clearance [9].
• We have examined the pharmacokinetics and disposition of L-692,429 in male Sprague-Dawley rats, beagle dogs, and chimpanzees [9].
• The growth hormone secretagogue, L-692,429, induces phosphatidylinositol hydrolysis and hormone secretion by human pituitary tumors [2].

Anatomical context of L-692429

• The non-peptidyl GH secretagogues L-692,585 and L-692,429 also induced Fos expression in the arcuate nucleus, and the pattern of distribution was similar to that described for GHRP-6 [10].

Associations of L-692429 with other chemical compounds

• However, the suppressive influence of the steroid was attenuated by the high dose of L-692,429, which achieved a GH peak and area under the curve between 0-240 min of 42.6 (5.8) micrograms/L and 2298 (425) micrograms/min.L, respectively (P < 0.01 vs. 0.2 mg/kg L-692,429 plus prednisolone) [7].
• These results indicate that L-692,429 and GHRP-6 stimulate GH release both in vitro and in vivo via a common receptor and signaling pathway which is different from that of substance P in spite of the fact that their effects are inhibited by a weak substance P antagonist [11].
• Using equimolar concentrations of thyrotropin-releasing hormone (TRH), human GH-releasing hormone (hGHRH1-29), and L-692,429 (10 nM), L-692,429 had 20-25% the in vitro potency of the two endogenous releasing factors [12].

Gene context of L-692429

• Growth hormone response in man to L-692,429, a novel nonpeptide mimic of growth hormone-releasing peptide-6 [13].
• Like GHRP-6, L-692,429 had no effect on intracellular cAMP level; however, it synergized with GRF to further increase not only the accumulation of cAMP but also the release of GH [14].
• The L-692,429-stimulated GH release was completely inhibited by 20 nM somatostatin [14].
• The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent [8].
• L-692,585 is a 2-hydroxypropyl derivative of L-692,429, both novel non-peptidyl growth hormone (GH) secretagogues [15].

References