Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related peptides which have numerous functions in both neural and endocrine signaling. By homology screening, we cloned a novel gene sharing the highest homology with the NPY Y1 receptor gene from humans, rabbits, and several other species. This novel gene of rabbit encodes a functional NPY/PYY receptor, designated Y2b, which prefers NPY 13-36 rather than [Leu 31 ,Pro 34 ]NPY despite its higher identity with the Y1 receptor. Although, at low levels, mRNA was detected in the tissues and brain regions, including hypothalamus. Further, sequence data revealed that this gene is the orthologue of the recently cloned mouse novel NPY receptor, Y5. However, our study demonstrates that the receptor function of this gene has been inactivated in primates by a frameshift mutation occurring early in primate evolution. This novel NPY receptor represents the first neurotransmitter receptor identified that has universally lost its receptor function in primate species. Interestingly, despite its inactivation in humans, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene.Neuropeptide Y (NPY), 1 peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related 36-amino acid peptides which have functions in both neural and endocrine signaling. These peptides exert their actions via receptors on the targeted neurons and peripheral cells. Several receptor subtypes have been defined by their ability to bind NPY, PYY, PP, and derivatives of these peptides. Earlier studies classified this receptor family into at least three receptor subtypes, Y1, Y2, and Y3 (1). The existence of additional receptors were also proposed, "atypical" Y1 receptor (mediating the feeding response of NPY in hypothalamus), PP-preferring receptor (exerting PP activity), and PYY-preferring receptor (2, 3). Molecular cloning studies have revealed the structure of Y1, Y2, and Y4/PP1 receptors (4 -9). These are all heptahelix (seven-transmembrane regions) receptors which couple to G-proteins. The Y4/PP1 receptor has higher affinity for PP than PYY and NPY, suggesting this receptor to be a member of PP receptors.As yet unknown members of this NPY receptor family are expected to be identified by molecular cloning. Very recently, during the course of the present work, the cloning and characterization of mouse Y5 (10) and rat Y5 (11) receptors was reported. The mouse Y5 receptor has significant homology with the Y1 receptor, but the rat Y5 receptor has little identity with the previously cloned NPY receptors, showing that these receptors are not species orthologues, despite having the same name, Y5. In the present report, we describe the cloning of a novel gene sharing the highest homology with the Y1 receptor from humans, rabbits, and several other species. Our study revealed that this novel gene is the orthologue of the mouse Y5 receptor gene (10) and encodes functional ...

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A series of N-[2-[(substituted chroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamines was prepared and examined for their 5-HT1A receptor antagonist activity. The parent compound 3a and seven analogs bearing five kinds of substituents on the chroman ring were prepared from the corresponding 8-hydroxychroman intermediates. Radioligand binding assays proved the compounds 3a-h to have high affinity for the rat hippocampal 5-HT1A receptor with varied selectivity for adrenaline alpha1 and dopamine D2 receptors. Their antagonism was evaluated in a forskolin-stimulated adenylate cyclase assay performed with CHO cells expressing the human 5-HT1A receptor. Among the series, the C6-fluoro analog 3c showed both extremely potent affinity (Ki = 0.22 nM) and antagonism (EC50 = 13 nM) for the 5-HT1A receptor. Correlation analysis using substituent descriptors revealed a linear and negative correlation between molar refractivity of the C6-substituent and the binding affinity expressed in pKi.

A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT1A receptor. N-2-[[(6-Fluorochroman-8-yl)oxy]ethyl]-4-(4-methoxyphenyl)butylami ne (3; J. Med. Chem. 1997, 40, 1252-1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect to alpha1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolin-stimulated adenylate cyclase assays in CHO cells expressing the human 5-HT1A receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1, 3-benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT-induced behavioral and electrophysiological responses in rats.