Neuropeptide Y receptors: Perspectives for the development of new drugs

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    It has proved difficult to use peptide tachykinin antag- onists as leads into low MW, orally active peptoid or non- peptide structures. Increasingly, random compound screening based approaches have been used, resulting in the first potent non-peptide NK, antagonists, CP96,345 (4) and RP 67580 (5). Interestingly, both demonstrate significant, but different variations inNK, receptor affinity between species. These and other non-peptide antagonists emerging in the literature, e.g. the NKJ antagonist, SR 48968 (6) should provide further insight into the role of tachykinins in the periphery and CNS.

    The availability of these antagonists, together with cloning and recombinant expression of the tachykinin receptor genes has substantiated the classification of tachykinin receptors into three types. To date, neither antagonist studies nor molecular biological approaches have provided conclusive evidence for further division of tachykinin receptors into subtypes occurring within a single species, but this remains an area of great speculation.







    Maggi, C. A., Guiliani, S., Ballati, L. et al. (1991). J. Phamxacol. and Exp. Ther. 257: 1172-l 178. M&night, A. T., Maguire, J. J., Elliott, N. J. et al. (1991). Br. J. Pharmacol. 104: 355-360. Hagan, R. M., Ireland, S. J., Bailey, F., McBride, C., Jordan, C. C. and Ward, P. (1991). Br. J. Pharmacol. 102: 168P. Snider, R. M., Constantine, J. W., Lowe, J. A. et al. (1991). Science 251: 435-437. Garrett, C., Carruette, A., Fardin, V. et al. (1991). Proc. Nat. Acad. Sci. (USA) 88: 10208-10212. Advenier, C., Emends-Alt, X., Vilain, P. et al. (1992). C92, Winter 1991 Meeting of British Pharmacological Society, London.

    Neuropeptide Y Receptors: Perspectives for the Development of New Drugs R. Hakanson* and L. Grundemart Dept. of *Pharmacology and TClinical Pharmacology, University of Lund, Sweden

    Neuropeptide Y (NPY) occurs in both the central and peripheral nervous system. In the periphery, NPY coex- ists with noradrenaline (NA) in perivascular sympathetic fibers and with vasoactive intestinal polypeptide (VIP) in neurons in e.g. the digestive tract, genitourinary tract and airways. NPY has a vasopressor effect, reflecting direct vasoconstriction of blood vessels and potentiation of the NA-evoked response. NPY also suppresses the release of NA from sympathetic fibers. The pre- and post-junctional effects of NPY are produced by interaction with distinct receptors, since C-terminal fragments evoke effects on pre-junctional but not on post-junctional sites. The post- andpre-junctional receptors were referred to as Y, and YZ,


    respectively. The Y, and Y2 receptors recognize not only NPY but also the homologous gut hormone peptide YY (PYY). The Y, and Yz receptors have been characterized in numerous test systems using analogues of NPY/PYY. The purpose was to identify which parts of the NPYIPYY molecule are required to activate the respective receptor type. The Y, receptor (blood vessels) accepts (Pro34)NPY as readily as NPY, but already the deletion of the first N- terminal aminoacid (NPY 2-36) results in a marked loss of potency. The Y2 receptor (vas deferens) is much less dependent upon an intact N-terminus, since a wide range of C-terminal NPY fragments (from NPY 2-36 to NPY 16-36) retain quite high potency. Experiments with cyclic and linear analogues with nonpeptide bridging constructs suggest that the mid-molecule portion (the so-called PP fold) is not essential for recognition by the YZ receptor and that the 12 C-terminal residues are sufficient to activate the receptor. (Pro34)NPY is inactive at the YZ receptor. Recently, an NPY receptor Y,, distinct from Y, and YZ in that it does not recognize PYY, has been demonstrated in the brain stem. Attempts to define the receptor types have relied on truncated and substituted analogues of NPY/PYY. Although such studies suggest the existence of at least three types of NPY receptors, the lack of antag- onists has represented a problem. The application of ratio- nal drag design to the development of antagonists to the Y, receptor or of superagonists of the YL receptors may introduce novel approaches in the therapy of hypertensive disorders.

    Differences in Affinities of Bradykinin BZ Receptor Antagonists may be Attributable to Species Judith M. Hall, Debra Mitchell, Sie Yan Chin, Julie L. Field, Christopher M. Everett and Ian K. M. Morton Pharmacology Group, Kings College London, SW3 6LX, UK

    Bradykinin (BK) mediates diverse actions through recep- tors of which two classes were originally proposed (6); namely B, receptors where C-terminal-deleted analogues (e.g. [des-Arg9]-BK) are active, and BZ receptors, the remainder, where these analogues are inactive. However, heterogeneity is evident within the Bz class (3); and recently a third class, B3, has been proposed to be present in airways. This latter site is relatively resistant to [D- Phe7]-BK substituted antagonist analogues active at Bj receptors (2).

    We have compared the affinities of BK receptor antag- onists in isolated tissue preparations in order to test the hypothesis that affinities of B2 antagonists form a contin- uum, within which B, receptors form a part, and where species is a major determinant of receptor properties. The Table shows some representative affinity estimates (p-42 or pKn) from this and other studies.


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