Acetalins (acetyl plus enkephalin) are a class of opioid receptor ligands. They were opioid receptor antagonists determined through the use of Synthetic Peptide Combinatorial Libraries
Dooley et al., in 1993 identified acetalins as a novel peptide antagonist to the mu receptor; through the use of combinatorial libraries. Deconvolution, or identification of individual compounds from the complex mixtures in the libraries, was achieved through an iterative process by using a positional scanning library1.
Enkephalins are pentapeptide involved in regulating nociception in the body. They are endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Acetalins are acetyl plus enkephalin. The sequence of Acetalins is Ac-RFMWMK-NH2 1. Acetalin 1, Opioid Receptor Antagonist 1 sequence is Ac - Arg - Phe - Met - Trp - Met - Arg - NH2. Acetalin 2, Opioid Receptor Antagonist 2 sequence is Ac - Arg - Phe - Met - Trp - Met - Lys - NH2. Acetalin 3, Opioid Receptor Antagonist 3, Ac - Arg - Phe - Met - Trp - Met - Thr - NH2 1.
Mode of Action
Enkephalins families of opioid peptides are produced by the body. The receptors for enkephalin are the opioid receptors. These are G-protein-coupled receptors, with other opioids as ligands as well. The other endogenous opioids are dynorphins, endorphins, endomorphins, and nociceptin/orphanin FQ. Enkephalin inhibit ganglionic transmission by both pre- and post-synaptic actions in a mammalian parasympathetic ganglion 2. ORL1 receptors have a very high homology with the opioid receptors 3. Acetalins were found to bind poorly (.15,000 nM) to ORL1 in mu, delta and kappa opioid receptor assays 4. Acetalin 1 peptide has a high affinity for m (IC50 = 1.1 nM, Ki = 0.5nM) and k3 (IC50 = 2.6 nM, Ki = 1.4nM) opioid receptors. Acetalin 2 peptide has also a high affinity for m (IC50 = 1.9 nM, Ki = 0.4 nM) and k3 (IC50 = 0.7 nM, Ki = 0.4 nM) opioid receptors. Acetalin 3 peptide also shows a high affinity for m (IC50 = 1.7 nM, Ki = 0.8 nM) and k3 (IC50 = 1.0 nM, Ki = 0.6 nM) opioid receptors 1. Normally, acetalins can be assumed to control inhibitory mechanisms determining the rate of neurotransmitter release. If, however, opiates are administered with the intent of increasing the effects of these inhibitory mechanisms, then control will pass from the endogenous enkephalin to the exogenous opiates 5.
Affinity, acetalin ligands display a high affinity for m and k3 receptors, a weaker affinity for a receptors and no affinity for k2 receptors 6.
Mood and motivation, endorphins released from nerve endings of the central nervous system and the adrenal medulla act as analgesics and sedatives in the body and appear to affect mood and motivation.
An opium-based drug, brain releases endorphins and enkephalins. Enkephalins block pain signals in the spinal cord and these morphine-like substances whose functions are similar to those of opium-based drugs 6.
Natural pain killer, the naturally occurring opiates include enkephalins (methionine and leucine), endorphins (alpha, beta, gamma, and delta) and a growing number of synthetic (artificial) compounds are used as natural pain killer.
1. Dooley CT, Chung NN, Schiller PW, Houghten RA (1993). Acetalins:Opioid receptor antagonists determined through the use of synthetic peptide combinatorial libraries. PNAS., 90:10811-10815.
2. Katayama Y, Nishi S (1984). Sites and mechanisms of actions of enkephalin in the feline parasympathetic ganglion. J Physiol., 351:111-121.
3. Mollereau C, Parmentier M, Mailleux P, Butour JL, Moisand C, Chalon P, Caput D, Vassart G, Meunier JC (1994). ORL1, a novel member of the opioid receptor family: Cloning, functional expression and localization. FEBS Lett., 341:33–38.
4. Dooley CT, Spaeth CG, Berzetei-Gurske IP, Craymer K, Adapa ID, Brandt SR, Houghten RA, Toll L (1997). Binding and in vitro activities of peptides with high affinity for the nociceptin/orphanin FQ receptor, ORL1. J Pharmacol Exp Ther., 283(2):735-741.
5. Waterfield AA, Hughes J, Kosterlitz HW (1976). Cross tolerance between morphine and methionine-enkephalin. Nature, 260(5552):624-625.
6. 8) Hughes MD, Zhang ZR, Sutherland AJ, Santos AF, Hine AV (2005). Discovery of active proteins directly from combinatorial randomized protein libraries without display, purification or sequencing: identification of novel zinc finger proteins. Nucleic Acids Res., 33(3):32.
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