Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.

The nature of the interaction of aminoacridines and their derivatives with nucleic acidst continues to engage the attention of investigators employing many different techniques. This interest persists for various reasons. First, the aminoacridines are themselves important antibacterial and mutagenic agents. Their antibacterial action has long been the subject of intensive study1+ but in the last six years it is their ability to induce mutations, apparently by causing deletion or insertion of a single nucleotide in DKA, which has been to the f~r e .~,~ This hypothesis has been convincingly confirmed6 by amino acid sequence determinations on lysozyme altered by a double mutation which was induced by proflavine (3,Gdiaminoacridine) in bacteriophage T4. This ability to interact with DNA must also form part, at least, of the explanation of their antibacterial activity and has been associated with their inhibition of DNA-primed DNA and RNA polymerases.7*8 However, this inhibition of RNA polymerase nou-appearsg also to involve a direct inhibition of the enzyme by the aminoacridine, and, indeed, aminoacridines are known to inhibit a number of enzymes' notably those involved in oxidation-reduction reactions. So the antibacterial activity of aminoacridines is likely to depend on a wider range of effects than simply their interaction with the nucleic acids.Second, aminoacridines, on account both of their cationic charge and their three flat aromatic rings, have structural features similar to those of other compounds whose interaction with DNA is of great interest, such as carcinogens (both polycyclic hydrocarbons and benzacridines) ; certain antibiotics; nucleic acid derivatives (purines, nucleosides) ; histological dyes, e.g., those with three flat, fused rings such as pyronin, toluidine blue. and triphenylmethane dyes such as methyl green; phenanthridine trypanocides, e.g., ethidium bromide; and, of course, other acridine derivatives. many of which are noted for their antimalarial activity, e.g., atebrin.Bedfordshire, England.

Somatostatin (SRIF) regulates pancreatic insulin and glucagon secretion. In the present study we describe the generation of SRIF receptor subtype 5 knockout (sst(5) KO) mice to examine the role of SRIF receptor subtypes (sst) in regulating insulin secretion and glucose homeostasis. Mice deficient in sst(5) were viable, fertile, appeared healthy, and displayed no obvious phenotypic abnormalities. Pancreatic islets isolated from sst(5) KO mice displayed increased total insulin content as compared with islets obtained from wild-type (WT) mice. Somatostatin-28 (SRIF-28) and the sst(5)/sst(1)-selective agonist compound 5/1 potently inhibited glucose-stimulated insulin secretion from WT islets. SRIF-28 inhibited insulin secretion from sst(5) KO islets with 16-fold less potency while the maximal effect of compound 5/1 was markedly diminished when compared with its effects in WT islets. sst(5) KO mice exhibited decreased blood glucose and plasma insulin levels and increased leptin and glucagon concentrations compared with WT mice. Furthermore, sst(5) KO mice displayed decreased susceptibility to high fat diet-induced insulin resistance. The results of these studies suggest sst(5) mediates SRIF inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity. Our findings suggest a potential beneficial role of sst(5) antagonists for alleviating metabolic abnormalities associated with obesity and insulin resistance.

Recently the genes for several hormone receptors that interact with guanine nucleotide binding proteins (G proteins) have been cloned, including the hamster beta 2-adrenergic receptor (beta 2AR), a human beta AR, the turkey erythrocyte beta AR and the porcine muscarinic acetylcholine receptor (MAR). All these receptors share some amino-acid homology with rhodopsin, particularly in 7 hydrophobic stretches of residues that are believed to represent transmembrane helices. To determine whether differences in ligand specificity result from the divergence in the sequences of the hydrophilic regions of these receptors, we have expressed in mammalian cells genes for the wild-type hamster and human beta AR proteins, and a series of deletion mutant genes of the hamster beta 2AR. The pharmacology of the expressed receptors indicates that most of the hydrophilic residues are not directly involved in the binding of agonists or antagonists to the receptor. In addition, we have identified a mutant receptor that has high agonist affinity but does not couple to adenylate cyclase.