CA2224066A1 — Peptides as analgesics

USPTO Abstract

No effective remedy exists for the treatment of chronic pain resulting from inflammation and neuropathy. The adrenal medullary peptide, histogranin (HN), and its chemically stable analogue, [Ser1]HN, alleviate the same type of pain as that blocked by spinal adrenal medullary implants. However, the administration of these peptides is more advantageous than the transplantation of adrenal medullary tissues or chromaffin cells into the spinal cord. In addition, the structure of HN peptides can be modified to improve their efficacy and length of action while avoiding the side-effects of opioid analgesics, aspirin derivatives and non-steroidal antiinflammatory agents. The HN fragment-(7-10), Gly-Gln-Gly-Arg (SL-99), is an analgesic as potent as the parent peptide HN in the mouse writhing pain assay. Its analogues, [Ala9]HN-(7-10) (SL-100: Gly-Gln-Ala-Arg) and [Arg7, Ala9]HN-(7-10) (SL-101: Arg-Gln-Ala-Arg), cyclo-(SL-100) (or SL-102) and the parent peptide [Ser1, Ala9]HN (SL-104: Met-Asn-Tyr-Ala-Leu-Lys-Gly-Gln-Ala-Arg-Thr-Leu-Tyr-Gly-Phe), show improved potency as compared with HN. The linear and cyclic forms of SL-100 and SL-101 are presented with the following general Formulae: (see fig. I) (see fig. II) wherein R1, R2, R3, R4, R5 and R6 are H (SL-100) or (CH2)2-NH2 (SL-101), (CH2)3-NH-C(=NH)-NH2, CH3, (CH2)2-NH2 H and H, respectively, or related substituents. The pharmaceutically-acceptable salts, esters and amides comprised in formulae I and II compounds, which are useful for inducing analgesia in animals, and a method for inducing analgesia in an animal in need thereof comprising administering a therapeutically-effective amount of Formula I or Formula II compounds to the animal.