Analogues of Somatostatin Bind Selectively to Brain Somatostatin Receptor Subtypes

Somatostatin (SRIF) is a neurotransmitter that produces its multiple effects in the CNS through interactions with membrane‐bound receptors. Subtypes of SRIF receptors are found in the CNS that are distinguished by their sensitivities to the cyclic hexapeptide MK‐678, such that SRIF, receptors are sensitive to MK‐678 and SRIF 2 receptors are insensitive to MK‐678. In the present study, we further examined the selectivities of a series of structurally diverse SRIF analogues for SRIF receptor subtypes. SRIF receptors were labeled by 125 I‐Tyr 11 SRIF, which has indistinguishable affinities for SRIF receptor subtypes. The inhibition by MK‐678 was incomplete, indicating this peptide is highly selective for a subtype of SRIF receptor that we have termed the SRIF, receptor. The binding of 125 I‐MK‐678 to SRIF, receptors was monophasically inhibited by SRIF, the octapeptides (such as SMS‐201–995), and the hexapeptides (such as MK‐678), consistent with the highly selective labeling of a subtype of SRIF receptor. In contrast, the smaller CGP‐23996‐like analogues did not inhibit 125 I‐MK‐678 binding to SRIF, receptors. The binding of 125 I‐CGP‐23996 to SRIF receptors was inhibited by SRIF and the octapeptides with Hill coefficients of < 1, indicating that 128 I‐CGP‐23996 labels multiple SRIF receptor subtypes. The hexapeptides and CGP‐23996‐like compounds produced only partial inhibitions of 125 I‐CGP‐23996 binding, which were additive, indicating selective interactions of these compounds with the different receptor subpopulations labeled by 125 I‐CGP‐23996. 125 I‐Tyr 11 ‐SRIF binding and 125 I‐CGP‐23996 binding to SRIF receptors were likewise only partially affected by 100 μ M guanosine 5′‐ O ‐(3‐thiotriphosphate) (GTPγS), a concentration that completely abolishes specific 125 I‐MK‐678 binding to SRIF, receptors. The component of 125 I‐CGP‐23996 labeling that was sensitive to GTPγS was also MK‐678 sensitive. Thus, two subpopulations of SRIF receptors exist in the CNS. The SRIF, receptor is sensitive to cyclic hexapeptides such as MK‐678 and to GTPγS but insensitive to smaller CGP‐23996‐like compounds. The SRIF 2 receptor is sensitive to the CGP‐23996‐like compounds and can be selectively labeled by 125 I‐CGP‐23996 in the presence of high concentrations of the hexapeptides or GTPγS because, unlike the SRIF, receptor, the SRIF 2 receptor is insensitive to these agents. The SRIF receptor subtype‐selective peptide analogues will be useful in the future characterization of the functions mediated by SRIF receptor subtypes in the CNS.