During the year the receptor pharmacology and molecular pharmacology of a number of gastrointestinal hormones/ neurotransmitters and growth factors was investigated including members of the PACAP-VIP family and bombesin receptor family (GRPR, NMBR, BRS-3) as well as publishing a number of expert opinions of advances in this field. For the first time the molecular basis of selectivity of a newly described BRS-3 receptor antagonist, Bantag-1, was determined and published, which should help in the design of future selective ligands for this receptor. Furthermore, the pharmacological selectivity of newly described chiral diazepine antagonists for the BRS-3 receptor over the closely related GRPR and NBMR was determined. In the case of the PACAP-VIP family of peptides, three receptors mediate their actions (VPAC1, VPAC2, PAC1), however no PAC1 specific ligands exist. The VIP replaed receptor, PAC1 has marked neuroprotective, neuroregenerative effects as well as anti-inflammatory effects and there is considerable need for a PAC1 selective agonist. In collaboration with Prof David Coy, Tulane University, 46 analogues of PACAP/VIP were synthesized, primary conformationally restricted in areas that are known to be important for agonist activity. A number of analogues were selective more than 80 fold for PAC1 over the VPAC2. These analogues will be important for defining PAC1s role therapeutically and in diseases.
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