Merck + Co., Inc.

Kenneth S Koblan

David A Claremon

Nigel J Liverton

Angus Murray MacLeod

Kevin John Merchant

John W Butcher

David G Melillo

Thomas M Connolly

Jackson B Gibbs

Christopher A Salvatore

David L Pompliano

Dennis C Dean

Jerzy Karczewski

Stefanie A Kane

Kevin R Oliver

Matthew J Kostura

John J Mallee

Disclosed herein are isolated nucleic acid molecules encoding a humanized version of a calcitonin gene-related peptide (CGRP) receptor, which comprises the G-protein coupled receptor calcitonin-receptor-like receptor (CRLR) and the receptor-activity-modifying protein 1 (RAMP1). The humanized CGRP receptors of the present invention attain pharmacological profiles similar to the wild type human receptor via modifications to the respective mammalian RAMP1 nucleotide sequence, specifically at amino acid 74. Also described are related recombinant vectors, recombinant hosts and associated methods for generating such humanized CGRP receptors. Also presented are non-human transgenic animals which express humanized RAMP1. Such animals have been engineered to provide for a CGRP pharmacological profile similar to human CGRP.

Isolated DNA molecules encoding humanized calcitonin gene-related peptide receptor, related non-human transgenic animals and assay methods

The present invention is directed to the radioligand compound, [S]-radiolabeled (+)-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydoxyspiro[2H-1-benzopyran-2,4&#x2032;-piperidin]-6-yl]methanesulfonamide. Also within the scope of this invention is a method for identifying compounds that bind to the Ichannel, and may have antiarrhythmic activity.

Radioligand and binding assay

Novel .alpha.-hydroxyphosphonate compounds which inhibit mammalian phosphoinositide-specific phospholipase-C. The compounds are potent anti-inflammatory and analgesic agents and may be useful for the treatment of cancer.

Inhibitors of phosphoinositide-specific phospholipase C

The present invention is directed to an assay which is used to determine the inhibitory activity of a test compound against a particular phosphoinositide-specific phospholipase C enzyme, that enzyme being phospholipase C.gamma.. The present invention is also directed to the preparation of phospholipase C.gamma. by recombinant expression in a bacterial cell and isolation of the expressed enzyme.

Expression and purification of phosphoinositide-specific phospholipase

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Carversville, PA, United States of America

Kenneth S Koblan