| Abstract
| - In the pursuit of potent analogues of neuropeptide Y (NPY) thatare selective for the Y1 receptorsubtype, two lactam bridge scans of a centrally truncated parentcompound were synthesized.A single lactam bridge (γ-carboxyl of Glu to ε-amino of Lys)extending from residues i to i + 3or i to i + 4 of the proposed α-helicalregion (residues 25−31 of NPY) was introduced in des-AA−[Gly6]NPY.Cyclogues (contraction of cyclic analogues), which wereapproximately one-half the size of native NPY, were initially screened for bindingaffinity at two discrete NPYreceptor types using human neuroblastoma cell membranes, SK-N-MC andSK-N-BE2.Exploitation of the subtle differences present on each receptortype allowed for the identificationof cyclogues which bound specifically to Y1 receptors withincreased affinity when compared tothe corresponding linear parent analogue, while one shortY1 specific cyclogue,des-AA2,3,5,7-24cyclo(26/29)[Gly6,Glu26,Lys29,Pro34]NPY,bound with Ki = 16 nM. Other cycloguesshowed distinctpreference for Y2 receptors and bound in the low-nanomolarrange. Functionally, the compoundsinhibited the norepinephrine-stimulated accumulation of cAMP indicatingthat all acted asagonists with varying potencies.
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