Insulin derivatives, biological activity

M. Hashimoto, K. Takada, Y. Kiso, S. Muranishi, Synthesis of Palmitoyl Derivatives of Insulin and Their Biological Activities , Pharm. Res. 1989, 6, 171 - 176. 

Hormones are intercellular messengers. They are typically (1) steroids (e.g., estrogens, androgens, and mineral corticoids, which control the level of water and salts excreted by the kidney), (2) polypeptides (e.g., insulin and endorphins), and (3) amino acid derivatives (e.g., epinephrine, or adrenaline, and norepinephrine, or noradrenaline). Hormones maintain homeostasis—the balance of biological activities in the body for example, insulin controls the blood glucose level, epinephrine and norepinephrine mediate the response to the external environment, and growth hormone promotes normal healthy growth and development. 

The difficulty with HLB as an index of physicochemical properties is that it is not a unique value, as the data of Zaslavsky et al. (1) on the haemolytic activity of three alkyl mercaptan polyoxyethylene derivatives clearly show in Table 1. Nevertheless data on promotion of the absorption of drugs by series of nonionic surfactants, when plotted as a function of HLB do show patterns of behaviour which can assist in pin-pointing the necessary lipophilicity required for optimal biological activity. It is evident however, that structural specificity plays a part in interactions of nonionic surfactants with biomembranes as shown in Table 1. It is reasonable to assume that membranes with different lipophilicities will"require" surfactants of different HLB to achieve penetration and fluidization one of the difficulties in discerning this optimal value of HLB resides in the problems of analysis of data in the literature. For example, Hirai et al. (8 ) examined the effect of a large series of alkyl polyoxyethylene ethers (C4,C0, Cj2 and C 2 series) on the absorption of insulin through the nasal mucosa of rats. Some results are shown in Table II. 

Structure-Activity Correlations. This detailed knowledge of the three-dimensional structure of insulin led to the recognition that its biological activity resides in an area of the molecule rather than in specific amino acid residues, just as dimerization and further association of the molecule also depend on an intact spatial structure. The foregoing concept is corroborated by structural modifications of the hormone. The last three amino acids of the B chain can be removed without a loss of activity, but cleavage of the C-terminal of the A chain (Asn ) results in a total loss of activity. Amino acids can be replaced inside the chains only if such substitution does not change the overall geometry of the molecule. The structure-activity relationships of insulin derivatives are inconsistent and not always comparable. 

McCusker R. H., McCrea K., Zunich S., Dantzer R., Broussard S. R., Johnson R. W., and Kelley K. W. (2006). Insulin-like growth factor-I enhances the biological activity of brain-derived neurotrophic factor on cerebrocortical neurons. J. Neuroimmunol. 179 186-190. 

Hashimoto, M., et al. 1989. Synthesis of palmitoyl derivatives of insulin and their biological activities. Pharm Res 6 171. 

The natural product asterriquinone Al (41) and asterriquinone derivatives containing the 3-indolylbenzoquinone structure exhibit a wide spectrum of biological activities, including antitumor properties, inhibition of HIV reverse transcriptase and as an orally active nonpeptidyl mimetic of insulin... 

Table X. Biological Activity of Human Insulin Derivatives...

Despite the marked conformity in the insulin binding curves of the insulins derived from different species and exposed to one anti-pig-insulin-antiserum, a marked discrepancy between immunological inhibition of biological activity and radio-immunologi-cally measurable insulin was noted. In contrast to the well known incomplete inhibition of the biological activity of serum insulin effected by antibodies, insulin activity in the incubation medium... 

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