nonpeptide somatostatin analogs: recent advances in its application and research

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Journal of Medical Colleges of PLA 23 (2008) 364–376

Nonpeptide somatostatin analogs: recent advances in its application and research

Wang Song1, Liang Qingmo1*, Liao Duanfang2 1Department of Oncological Surgery, Nanhua Hospital, University of South China, Hengyang

421002, Hunan, China

2Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, Hunan, China

Received 15 September 2008; accepted 3 November 2008

Abstract

Along with its wide anatomical distribution, somatostatin (SST) acts on multiple targets via a family of 5 receptors to produce a broad spectrum of biological effects. Therefore, a variety of peptide analogs have been produced and are widely used in clinical treatment. However, because of their flaws in the structure of peptide, the clinical efficacy is limited. In this review, we summarize the structure, pharmacological effects and the potential clinical value of non-peptide SST analogs. We focus on the research and development of non-peptide SST analogs since 1998, and discuss the problems and potential prospects for non-peptide SST analogs. We believe that as more non-peptide somatostatin analogs are successfully developed, the extensive clinical application of SSTs will contribute a great deal to medical science. Keywords: Nonpeptide somatostatin; Structure; Pharmacological study; Potential clinical value

1. Introduction

Naturally occurring somatostatin (SST) is a regulatory small peptide, which was originally isolated from the ovine hypothalamus in 1973. It has 2 known biologically active forms, a 14-mer (SST-14) and a 28-mer N-terminal extended form

(SST-28), both of which originate from the same precursor (the 92-peptide somatostatin precursor) by hydroxylation. By negative regulation of hormones, SST affects the function of many important biological systems, including the endocrine, gastrointestinal, vascular, and immune systems along with the central and peripheral nervous systems.

Although SST is widely distributed and has diverse roles, it also has a very short biological half-life (less than 3 min). Therefore, identification of possible peptide skeleton structure modification is important for so-called peptide somatostatin

* Corresponding author.

Tel.: 86-734-83580861; Fax: 86-734-83583991 E-mail address: [email protected] (Liang Q.)

Wang Song et al. / Journal of Medical Colleges of PLA 23 (2008) 364–376 365

analogs (SSTA) to prevent degradation via shuttle-peptidase and amino-peptidase. Currently, there are several synthetic peptide somatostatin analogs, including the eight peptide analogs octreotide (SMS 201-995), lanreotide (BIM 23014) and vaprotide (RC160); the seven peptide analog TT-232; and the 6 peptide analog seglitide (MK-678). Compared with SST, SSTAs have clinical advantages including a longer biological half-life (90 min), higher performance, metabolic stability. They are more selective, and are smaller molecules.

However, in clinical use, peptide somatostatin analogs also suffer from numerous limitations, including lack of oral bioactivity, relatively short plasma half-life (less than 120 min), poor penetration of the blood-retinal barrier and blood-brain barrier to access the central nervous system, and its immunogenicity. Therefore, in addition to improving the optimization of the peptide structure and preparation, research and development of new structure types and improved efficiency have been a focus of research in recent years. In this paper, we would like to discuss a new vision of somatostatin analogs—the non-peptide somatostatin analogs that have been developed since 1998.

2. Chemical structure of non-peptide SST analogs

Non-peptide SST analog is a small protein-like chain designed to mimic somatostatin (peptidomimetic), containing non-peptidic structural elements that is capable of binding to and activating somatostatin receptors (SSTRs), and mimicking or antagonizing the biological role of SST. Overall, non-peptide SSTs analogs are particularly advantageous because they can selectively bind to SSTRs, long half-life, high membrane permeability, oral bioavailability, are well tolerated, have a high utilization rate and are

non-immunogenic. Therefore, non-peptide SST analogs are becoming more attractive to researchers.

In 1998, Rohrer et al [1] reported on a cyclic hexapeptide SST agonist (L-363,377), which was developed as a molecular probe, in a research of integrated approach of combinatorial chemistry and high-throughput receptor-binding techniques to rapidly identify subtype-selective compounds. Us- ing these techniques, the authors found that a number of highly selective non-peptide SST analogs could bind to various SST receptor (SSTR) subtypes, including L-797,591 (SSTR1), L-779,976 (SSTR2), L-796,778 (SSTR3), L-803,087 (SSTR4) and L-817,818 (SSTR5) (Fig. 1). These findings started a new era for non-peptide SST research and development.

In the following decade, based on the known molecular model of SST, a range of non-peptide SST analogs have been developed, and most of them have been patented, such as US6387932, US6861430, US6352982, US6221870, US6159941, US6777408 [2–16]. See Table 1.

In this table, from patent US 6861430, BN81644 chemical structure is (3R)-1,1-dibutyl- 3-(4-benzene-4-yl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H- -carboline and BN81674 is (3R)-1, 1-Diamyl-3-(4-benzene-4-yl-1H-imidazol-2-yl)-2, 3,4,9-tetrahydro-1H- -carboline; In patent US 6221870, SRA880 chemical structure is [3R, 4aR,10aR]-1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-1-methyl-benz[g]-quinoline-3-carboxylic-acid-4-(4-nitro-phenyl)-piperazine-amide, hydrogen ma- lonate; and, for patent US 6159941, NNC 26-9100 chemical structure is 1-(3-(N-(5-Bromo-pyridin-2- yl)-N-(3,4-dichlorobenzyl)amino)propyl)-3-(3-(1H- imidazol-4-yl)propyl)thiourea.

3. Pharmacological studies

3.1. Ligand-binding assays

The basic principle of ligand-binding studies

366 Wang Song et al. / Journal of Medical Colleges of PLA 23 (2008) 364–376

is the application of radionuclide-tagged specific ligands and receptor-binding, and a combination of competitive principles to determine the affinity and quantity of non-peptide SST analogs to the SSTRs. In brief, the first mammalian expression vectors containing the full-length coding sequences for hSSTR1–5 were constructed, and stably transfected into CHO-K1 or CCL19 cells using lipofectamine. Next cell membranes containing the SSTR1~5 receptor were incubated with 125I-Tyr11-SRIF and 125I-Tyr3 octreotide, for example. In the presence or absence of nonpeptide somatostatin, after repeatedly clearing the 125I-Tyr11-SRIF and

125I-Tyr3 octreotide, data from radioligand binding studies were used to generate inhibition curves, and IC50, Ki, and pKd values were obtained from curve-fitting performed with the mathematical modeling program FITCOMP. See Table 2.

3.2. Inhibition of forskolin-stimulated cAMP accumulation

The basic principle of this test is that adenosine phosphate (cAMP) accumulation in cells can be induced by forskolin, which can be inhibited

Fig. 1. Color-coding of SST receptor-selective compounds illustrates the relationship of various parts of eachmolecule to the original lead structure L-264,930 (Upper). Blue, green and red represent the aromatic group, tryptophan and diamine, respectively. L-797,591, L-779,976, L-796,778, L-803,087, and L-817,818 are selective for the SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, respectively (Lower) [1] .

H2N O

H N

NH

H2N

NH

NH

H

H N

L-797,591

N

L-779,976

O

HN

O

NHO

N

O

H2N

H3CO ONH

O

HN

O

O N H

N H

NO2

L-796,778

L-803,087 L-817,818

HN

F

NH

FH2N

O O O

H2N

NH2

HN

OOONH

N

N

OH

Molecularmodeling

HN

O

O

N H HN

Databasesearch

H2NH2N NH

NH O

O

N H N

O

L-363,377

HN

HN

NH

O O

L-264,930

O

HO

N


Table 1

Patents published for non-peptide SST analogs from 2000 to 2007

No. USPTO Patent/ USPTO Published Application

Formula

Core structure Selective SSTR

Date of Patent

1 US20030191134 US20040019092 US7189856 [2–4]

hydantoin

SSTR2

2003 2004 2007

2 US 6387932 [5]

SSTR2

2002

3 US 6861430 [6]

-carboline

SSTR3

2005

4 US 6352982 [7]

4,1-benzoxazepi-nes

SSTR5

2002

B R1

N 4 3

2 1

5 R4

R3

R2

N A

B R1

N4 3215R4

R3

R2

N6 Z1

Z2

Z3

R5

R5

or

NB A R88

R1 H N

O O

Z

N

R3 R4

Y

( )q

( )r

R4 N H

NH

R5N

R1

NH

R2R3

D E G Z

L R2 B

A

Y

N R1 X


Table 1 (Continued)


Formula


Date of Patent

5 US 6221870 [8] SRA880 [9]

ergoline

SSTR1

2001 2004

6 US6159941 [10]

X indicates S (thiourea) or NH (guanidine)

SSTR4

2000

7

US20070129313 [11]

Sulfonylation

SSTR1 SSTR4

2007

8

US20070129422 [12]

Sulfonylation

SSTR1 SSTR4

2007

R4NNO

H

R5

NR6

R3

R2 N

R1

O N O

N N O

H N

CH3H

( )

CH3 O

9

6

1

38 COOH

COOH

(CH2)n

A N

(CH2)

B

N R1 R2

N(CH2)p

X

D

R2S

NN N

(CH2)n

A

B R1

(CH2) (CH2)pD

R R2

R

R3

N

N N

S

D

O O

O

Q K

n

BA

B

R2

R1OSO

N

B

N N

O

O


Table 1 (Continued)


Formula


Date of Patent

9 US6602849 [13]

imidazole

SSTR1– SSTR5

2003

10 US 7238695 [14]

imidazole

SSTR1– SSTR5

2007

11 US 7015213 [15]

Pyrido-thieno-diazepines

SSTR1– SSTR5

2006

12 US 6777408 [16]

Pyrido-thieno-diazepines

SSTR1– SSTR5

2004

by the natural SST. Therefore, after incubating cells with the non-peptide SST compounds, a decrease or increase in cAMP levels will reveal whether the compound is a SST receptor agonist or an antagonist. In brief, SSTR1–5 receptor expression constructs and transfection were the

same as for the ligand binding assays (see 3.1; but the cell lines used are CHO-K1, COS-7, CCL39 or HEK). Then, cells were incubated without (control group) or with forskolin and various concentrations of the test compound. radioimmunoassay analysis of the cAMP content using the NEW/DuPont assay

R1

N a-(Y)n

R2 NR3

R4

R5

N

b-(Z)n

(CH2)m

O

X4

X3

X2

X1 (Z)n

(Y)a N R1

N

N

R2 R3

R4

R5

O

(CH2)m

or

R3

R5R4

R2 R1 R6

N

N N

R1

R2aR2b

N

N

NN

S N W

R3

R3a

R3b

A B

R2

NN R1

S

R4X


and the IC50 and ED50 were calculated. See Table 3. All of the above research shows that several

non-peptide SSTR agonists or SSTR antagonists, with activity for all types of SSTR, have research and clinical application.

3.3. Inhibition of Growth Hormone Release

The basic principle of this test is that somatostatin can inhibit the release of growth hormone, and a comparison can be made between the inhibition of growth hormone (GH) secretion in the control group and that achieved with the non-peptide SST analog. For this in vitro test, cells were isolated from rat pituitaries; then after

enzymatic digestion, humidification, culture and repeated washing, the cells were incubated with the non-peptide SST analog. The supernatant fluid was then removed and assayed for GH by radioimmunoassay. In addition, we can directly measure the serum levels of GH in rats or rhesus monkeys after injection of the non-peptide SST analogs, with results presented as hGH% or plasma GH concentrations.

Compound 45 was selected from the patents US20030191134, US20040019092 and US7189856 for testing. The study showed that it inhibits GH secretion in a dose-dependent fashion at doses of 0.1 to 1 mg/kg, and at 0–2 h hGH% was higher than for SRIF-14 (control group) [2–4]. See Fig. 2.

Table 2 Ligand-binding assays of non-peptide SST analogs


Affinity and quantity to the SSTRs

1 US20030191134 US20040019092 US7189856 [2–4]

SSTR2: IC50 =0.1–1×106 nmol/L

2 US 6861430 [6]: BN81644 [17] BN81674 [18]

SSTR3: Ki=0.64 nmol/L SSTR3: Ki=0.92 nmol/L

3 US 6352982 [7]: compounds 102 SSTR5: IC50=0.1 pmol/L 4 US 6221870 [8]: SRA880[9] SSTR1: pKds=5.84–6.02 5 US6159941 [10]: NNC26-9100 [19, 20] SSTR4: Ki=6 nmol/L 6 US20070129313 [11] : Compounds 2

Compounds 5 SSTR1: Ki=34±14 nmol/L SSTR4: Ki=1.2±0.4 nmol/L

All of the above researches showed that non-peptide SST analogs exhibited greater affinity to the SSTRs than natural SST, and had greater selectivity and specificity.

Table 3Inhibition of forskolin-stimulated cAMP accumulation of non-peptide SST analogs

NO. USPTO Patent/ USPTO Published Application

Antagonist/agonist to the SSTRs

1 US 6861430 [6] BN81644 [17] BN81674 [18]

SSTR3: IC50= 0.84 nmol/L antagonist SSTR3: IC50= 2.7 nmol/L antagonist

2 US 6352982 [7] compounds 102 compounds 5

SSTR5: ED50= 0.3 nmol/L antagonist SSTR5: ED50=0.7 nmol/L antagonist

3 US 6221870 [8] SRA880 [9] SSTR1: pKds=7.25–7.5 antagonist 4 US6159941 [10] NNC26-9100 [19, 20] SSTR4: ED50=26 nmol/L agonist


In another study, using Sprague-Dawley rats, compound 5 was selected from patent us6352982 for the treatment group (n=5), and methylcellulose was administered in the control group (n=4). The plasma GH concentrations were 11.2±6.5 ng/ml and 92.0±56.0 ng/ml respectively [7], suggesting that the GH level in the compound 5-treatment group was eight-times lower than in the control group.

4. Potential clinical value

SST, peptide somatostatin analogs and non-peptide SST analogs should all bind to specific SSTR to mediate their effects. There are five SSTR subtypes (SSTR1–5), which are unevenly distributed in the body and shown to have different pharmacological properties. Based on the structural similarity and reactivity for octapeptide and hexapeptide SST analogs, SSTR2, 3 and 5 belong to a similar SSTR subclass (SRIFI). SSTR1 and 4 interact poorly with these analogs and belong to a separate subclass (SRIFII); however, their function is poorly understood [21]. The following section of this review focuses on the known clinical applications of peptide somatostatin analogs, non-peptide SST analogs, and SSTR1–5, to explore the potential clinical value non-peptide SST analogs.

4.1. SSTR2-selective non-peptide SST analogs

SSTR2 agonists/antagonists can be used for the treatment and prevention of disorders in which somatostatin itself, or the physiological processes it regulates, is involved in mammals and humans. In this regard, SSTR2 may be involved in five distinct clinical settings.

(1) Activation of SSTR2 can suppress the secretion of certain hormones, including insulin, glucagon, prolactin, growth factors and other trophic factors. Therefore, SSTR2 can be targeted in the treatment of disorders associated with abnormal endocrine function. For example, Strowski et al [22] reported that L-054,522 inhibited glucagon secretion from pancreatic cells, which expressed SSTR2, whereas insulin secretion from cells, which expressed SSTR5, was not suppressed. In the fasting state, this can lower blood glucose by approximately 25%; therefore, by mimicking natural somatostatin, targeting SSTR2 could be of benefit in treating type 2 diabetes.

(2) Treatment of several hormone- dependent tumors by inhibiting the hormone secretions and trophic factors in mammals, including cancers of the breast, brain, prostate, and lung (both small cell and non-small cell epidermoids), as well as hepatomas, neuron-blastomas, colon and pancreatic adeno-carcinomas (ductal type), chondrosarcomas and melanomas. For example, Ma et al [23] found that octreotide induced the apoptosis of human hepatoma cells by the enhancing the Fas/FasL gene expression.

(3) Direct absorption via the digestive tract for treatment of gastrointestinal disorders. For example, Emery et al [24] reported that L-779,976 could cross the colonic epithelium and was 10 times more potent than octreotide as an inhibitor of fluid and electrolyte secretion, when the basolateral surface of the rat colon was increased, and was similar to that with GF120918 (a known inhibitor of

Fig. 2. The effect of compound 45 on GH plasma levels in rhesus monkey after subcutaneous administration in two-hour intervals [2–4].

Control

Compound

-1 0 1 2 3 4 5 6

200

175

150

125

100

75

50

25

0

hGH

%

Time (h)

1 10 100 g/kg s.c.


P-glycoprotein). In contrast, L-797591 (SSTR1), L-779976 (SSTR2), L-796778 (SSTR3), L-803087 (SSTR4) or L-817818 (SSTR5) showed little or no anti-secretory activity in this preparation.

(4) As an analgesic in pain modulation. For example, Ji et al [25] reported that, unlike opioids, the non-peptide imidazolidinedione SSTR2 agonist SCR007 was beneficial for the treatment of pain of peripheral and/or central origin by down-regulating the cAMP/PKA pathway.

(5) SSTR2 could be used for the treatment of ophthalmopathy. For example, Palii et al [26] reported that micromolar concentrations of RFE- 011, a non-peptide imidazolidin-2,4-dione SSTR2 agonist, could be administrated via intravitreal or transscleral routes for treatment of ocular neovascularization to ensure efficacious concentrations reached the target retinal and choroidal tissue.

4.2. SSTR5-selective non-peptide SST analogs

As for SSTR2, SSTR5 mediates similar physiological functions, so most of them have the same clinical roles. However, some distinct physiological activities have also been reported.

(1) Mitra et al [27] used double immuno- staining to show that SSTR5 was expressed exclusively in the cells of rat pancreatic islets and mediated insulin secretion, while the SSTR2A had been localized to rat pancreatic cells and mediated glucagon secretion. Thus both receptors had opposite functions in glucose regulation.

(2) Ke et al [28] studied the localization of SSTR5 by immunocytochemistry in rat retinal amacrine cells (ACs). SSTR5 was found to be diffusely distributed across the entire inner plexiform layer (IPL) and formed two distinct fluorescence bands in the distal part of the IPL. Double labeling experiments showed that it was highly expressed in GABAergic and dopaminergic Acs, expressed at a low level in cholinergic ACs,

while no SSTR5-immunoreactivity was found in glycinergic AII Acs. These results suggest that SSTR5 may serve as an autoreceptor or conventional receptor in retinal Acs, and its agonists/antagonists could be used for the treatment of ophthalmopathy through regulation of different- ergic cells 4.3. SSTR3-selective non-peptide SST analogs

Analogs under the patent US6861430 act as

SSTR3 (mainly distributed in the brain) antagonist and can be used for the treatment and prevention of mental illness in humans.

Troxler et al [6] reported that: (1) In the social exploration test,US6861430 increased the social contact time of rats. (2) In the mouse intruder test, US6861430 increased social investigation and reduced defensive ambivalence in the treated intruder mouse. (3) In the stress-induced hyperthermia and the elevated plus-maze paradigm in mice, US6861430 reduced the increase in body temperature and increased the time spent in the open arms, respectively. (4) US6861430 increased the exploratory behavior of mice in the open half of the half-enclosed platform, a model for anxiolytic activity. In the same half-enclosed platform model, US6861430 also increased vigilance of the mice. (5) Furthermore, in contrast to benzodiazepines, an advantage is that US6861430 does not impair memory, as measured in the passive avoidance test (a paradigm for memory formation impairment).

In short, the above findings suggest that US6861430 has a broad use for the treatment of mental illnesses, including anxiety, depression, social phobia, panic disorders, GAD (generalized anxiety disorders), OCD (obsessive compulsive disorders), ADHD (attention deficit and hyper- activity disorders), bipolar disorders and schizo- phrenia.


4.4. SSTR1-, SSTR4- and SSTR1/4-selective non- peptide SST analogs

(1) Research by Bito et al [29] showed that

SSTR4 was functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and the mitogen-activated protein (MAP) kinase cascade in hippocampal neurons, suggesting that its agonists might be used for prevention and treatment of various types of anxiety symptoms. Qiu et al [30] reported that because the K(+) M-current (I(M), Kv7) was an important regulator of cortical excitability, and mutations in these channels caused a seizure disorder in humans, SSTR4 coupling to M-channels was critical to its inhibition of epileptiform activity, suggesting that SSTR4 non-peptide agonists could offer novel antiepileptic and antiepileptogenic drugs.

(2) Research by Curtis et al [31] showed that human blood vessels (normal veins and arteries, as well as atherosclerotic arteries) predominantly expressed high levels of SSTR-1, and was present in endothelial but not vascular smooth muscle cells. In addition, ECV304 and human umbilical vein endothelial cells were investigated and shown to express only SSTR1 and 4, and not SSTR2, 3 and 5. Aavik et al [32] reported that CH275 (SST agonist selective for receptor subtypes 1 and 4) dose-dependently inhibited intimal hyperplasia after rat carotid denudation injury. Similarly, a study by Tigerstedt et al [33] showed that the an SSTR4-selective analog was more effective than an SSTR1-selective analog in inhibiting the percent of outgrowth and the migration of endothelial cells from the explants, while neither compound affected proliferation. The above results suggested that SSTR1/4 non-peptide agonists could be used for the treatment of vascular dysplasia.

(3) Mori et al [34] revealed that SSTR4 was a major subtype that was predominantly expressed in the rat iris epithelium/ciliary body and retina. They

found functional roles of SSTR4 non-peptide analogs in the autonomic nervous system in the anterior segments of the eye, so they could be used for the treatment and prevention of ophthalmopathy. In particular, such conditions that could be managed using SSTR4 non-peptide analogs include high intraocular pressure (IOP), glaucoma and/or deep ocular infections and stromal keratitis.

4.5. Others

(1) Combined: non-peptide somatostatin can be combined, or applied with non-peptide somatostatin analogs specific for SSTR1–5 (e.g., US7238695, US7238695, US7015213 and US677- 7408) to concurrently target multiple receptors and pathways to improve treatment of some diseases.

(2) Tumor-targeted radioactive treatment or diagnosis: in situ radiotherapy with radiolabeled non-peptide SST analogs can be used for scintigraphic evaluation and management of patients with SSTR-positive cancers [35].

(3) Receptor-targeted chemotherapy: Anti- cancer drugs linked to non-peptide SST analogs can be used for tumors in which treatment is targeted at cells that express the SSTR.

5. Discussion

Because of its high biological activity and well-characterized clinical value, non-peptide SST analogs are attracting increasing attention. In combination with the development of new combinatorial chemistry and screening technology its research and design speed is becoming more rapid, with great potential. However, it has a short history, and development of compounds is still rare. Without the completion of clinical trials, side effects and drug resistance remain unclear. Also, the pharmacophore could be utilized for development of second generation non-peptide SSTR analogs, as the structural optimization is still limited; this could improve the optimization and


receptor specificity of the non-peptide SST analogs.

Fortunately, ongoing studies focusing on the advantages of targeting specific SSTRs in various diseases, and the differences in SSTR expression between several diseases, will facilitate the clinical introduction of non-peptide somatostatin. For example, Taboada et al [36] used quantitative real-time RT-PCR to compare the absolute mRNA copy numbers for all five SSTR isoforms in somatotropinomas and non-functioning pituitary adenomas and revealed that SSTR5 mRNA was present at the highest level in somatotropinomas, followed by SSTR2>SSTR3>>SSTR1>>>SSTR4. In contrast, in non-functioning pituitary adenomas, the order of expression was SSTR3>SSTR2> SSTR1>SSTR4>SSTR5. Hagströmer et al [37] reported that healthy skin and lesioned skin from patients with atopic dermatitis or psoriasis showed many similarities, as they all expressed SSTR1–3 while it was noteworthy that SSTR4 and 5 were strongly expressed in the epidermis of psoriasis patients, but weakly expressed in the epidermis of those with atopic dermatitis and normal skin. Furthermore, the pharmacological characteristics, the pharmacophore, of non-peptide SST analogs are still being investigated. For example, Crider et al [38] suggested that thioureas, ureas, beta- glucosides, and sulfonamides, could serve as models for the binding affinity and selectivity to SSTR4.

We believe that, on the basis of the development of non-peptide SST analogs from 1998 to 2008 and with the ongoing research, non-peptide SST analogs will become a significant tool in the clinician’s armory. References 1. Rohrer SP, Birzin ET, Mosley RT et al. Rapid

identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science 1998; 282 (5389): 737–740.

2. Shapiro G, Natchus MG, Lockwood MA Jurczyk S, inventors. Non-peptide somatostatin receptor ligands. US patent 20030191134. 2003 October 9.

3. Berney D, Breckenridge R, Neumann P, Shapiro G,Seller MP, Thomas JT, inventors. Non-peptide somatostatin receptor ligands. US patent 20040019092. 2004 January 29.

4. Shapiro G, Natchus MG, Lockwood MA Jurczyk S, inventors. Non-peptide somatostatin receptor ligands. US patent 7189856. 2007 March 13.

5. Zhou C, Pasternak A, Morriello G, Guo L, Pan Y, Yang L, Patchett A, inventors; Merck & Co. Inc., assignee. Somatostatin agonists. US patent 6387932. 2002 May 14.

6. Troxler TJ, Hurth K, Hoyer D, inventors; Novartis AG, assignee. -carboline derivatives and its pharmaceutical use against depression and anxiety. US patent 6861430. 2005 March 1.

7. Mabuchi H, Suzuki N, Miki T, inventors. 4,1- benzoxazepines, their analogs, and their use as somatostatin agonists. US patent 6352982. 2002 March 5.

8. Pfaeffli P,Neumann P, Swoboda R,Stutz P, inventors. Novartis AG, assignee. Ergoline derivatives and their use as somatostatin receptor antagonists. US patent 6221870. 2001 April 24.

9. Hoyer D, Nunn C, Hannon J, et al. SRA880, in vitro characterization of the first non-peptide somatostatin sst(1) receptor antagonist. Neurosci Lett 2004; 361 (1–3): 132–135.

10. Ankersen M, Stidsen CE, Crider MA, inventors. Novo Nordisk A/S, assignee. Use of somatostatin agonists and antagonists for treating diseases related to the eye. US patent 6159941. 2000 December 12.

11. Tomperi J, Engstrom M, Wurster S, inventors. Siegfried Wurster, assignee. Sulfonylamino- peptidomimetics active on the somatostatin receptor subtypes 4 (sstr4) and 1 (sstr1). US patent 20070129313. 2007 June 7.

12. Tomperi J, Hautamaki P, Salo H, Engstrom M, Tauber A, Hoffren AM, Wurster S, inventors. OY Juvantia Pharma LTD, assignee. Somatostatin


receptor 1 and/or 4 selective agonists and antagonists. US patent 20070129422. 2007 June 7.

13. Gordon TD, inventors. Societe de Conseils de Recherche etd’, Applications Scientifiques, S.A.S, assignee. Cyclic somatostatin analogs. US patent 6602849. 2003 August 5.

14. Thurieau CA, Poitout LF, Galcera MO, Moinet CP, Gordon TD, Morgan BA, inventors. Societe de Conseils de Recherche etd’, Applications Scientifiques, S.A.S, assignee. Imidazolyl derivatives. US patent 7238695. 2007 July 3.

15. Bigg D, Liberatore AM, Pommier J, Taylor J, inventors. Societe de Conseils de Recherche etd’, Applications Scientifiques,(S.C.R.A.S), assignee. Use of diazepines for preparing medicines for treating pathological conditions or diseases involving one of the growth hormone release inhibiting factor receptors. US patent: 7015213. 2006 March 21.

16. Liberatore AM, Bigg D, inventors; Societe de Conseils de Recherche etd’, Applications Scientifiques, (S.C.R.A.S), assignee. Pyrido- thieno-diazepines method for the production thereof and pharmaceutical compositions containing said pyrido-thieno-diazepines. US patent 6777408. 2004 August 17.

17. Poitout L, Roubert P, Contour-Galcéra M O, et al. Identification of potent non-peptide somatostatin antagonists with sst (3) selectivity. J Med Chem 2001; 44 (18): 2990–3000.

18. Moinet C, Contour-Galcéra MO, Poitout L, et al. Novel non-peptide ligands for the somatostatin sst3 receptor. Bioorg Med Chem Lett 2001; 11 (8): 991–995.

19. Liu S, Tang C, Ho B, et al. Nonpeptide somatostatin agonists with Sst4 selectivity: synthesis and structure-activity relationships of thioureas. J Med Chem 1998; 41 (24): 4693–4705.

20. Liu S, Crider AM, Tang C, et al. 2-pyridylthioureas: novel nonpeptide somatostatin agonists with SST4 selectivity. Curr Pharm Des 1999; 5 (4): 255–263.

21. Reisine T, Bell GI. Molecular biology of somatostatin receptors. Endocr Rev 1995; 16 (4): 427–442.

22. Strowski MZ, Cashen DE, Birzin ET, et al. Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype-2 agonist. Endocrinology 2006; 147 (10): 4664–4673.

23. Ma Q, Meng L Q, Liu J C, et al. Octreotide induces apoptosis of human hepatoma cells by the mechanism of facilitating the Fas/FasL gene expression therein. Zhonghua Yi Xue Za Zhi 2008; 88 (10): 716–718. (In Chinese)

24. Emery PT, Higgs NB, Warhurst AC, et al. Anti-secretory properties of non-peptide somatostatin receptor agonists in isolated rat colon: luminal activity and possible interaction with P-glycoprotein. Br J Pharmacol 2002; 135 (6): 1443–1448.

25. Ji GC, Zhou ST, Shapiro G, et al. Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist: in vitro and in vivo studies in rat. Pain 2006; 124 (1–2): 34–49.

26. Palii SS, Afzal A, Shaw LC, et al. Non-peptide somatostatin receptor agonists specifically targeting ocular neovascularization via the somatostatin type 2 receptor. Invest Ophthalmol Vis Sci 2008. [Epub ahead of print].

27. Mitra SW, Mezey E, Hunyady B, et al. Colocalization of somatostatin receptor sst5 and insulin in rat pancreatic -cell. Endocrinology 1999; 140 (8): 3790–3796.

28. Ke JB, Zhong YM. Expression of somatostatin receptor subtype 5 in rat retinal amacrine cells. Neuroscience 2007; 144 (3): 1025–1032.

29. Bito H, Mori M, Sakanaka C, et al. Functional coupling of SSTR4, a major hippocampal somatostatin receptor, to adenylate cyclase inhibition, arachidonate release and activation of the mitogen-activated protein kinase cascade. J Biol Chem 1994; 269 (17): 12722–12730.

30. Qiu C, Zeyda T, Johnson B, et al. Somatostatin receptor subtype 4 couples to the M-current to regulate seizures. J Neurosci 2008; 28 (14): 3567–3576.

31. Curtis SB, Hewitt J, Yakubovitz S, et al. Somatostatin receptor subtype expression and function in human vascular tissue. Am J Physiol


Heart Circ Physiol 2000; 278 (6): H1815–H1822.32. Aavik E, Luoto NM, Petrov L, et al. Elimination of

vascular fibrointimal hyperplasia by somatostatin receptor 1,4-selective agonist. FASEB J 2002; 16 (7): 724–726.

33. Tigerstedt NM, Aavik E, Aavik S, et al.. Vasculoprotective effects of somatostatin receptor subtypes. Mol Cell Endocrinol 2007; 279 (1–2): 34–38.

34. Mori M, Aihara M, Shimizu T. Differential expression of somatostatin receptors in the rat eye: SSTR4 is intensely expressed in the iris/ciliary body. Neurosci Lett 1997; 223 (3): 185–188.

35. Müller C, Forrer F, Bernard B F, et al. Diagnostic versus therapeutic doses of [(177)Lu-DOTA- Tyr(3)]-octreotate: uptake and dosimetry in somatostatin receptor-positive tumors and normal organs. Cancer Biother Radiopharm 2007; 22 (1):

151–159.36. Taboada GF, Luque RM, Bastos W, et al.

Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. Eur J Endocrinol 2007; 156 (1): 65–74.

37. Hagströmer L, Emtestam L, Stridsberg M, et al. Expression pattern of somatostatin receptor subtypes 1-5 in human skin: an immunohisto- chemical study of healthy subjects and patients with psoriasis or atopic dermatitis. Exp Dermatol 2006;15 (12): 950–957.

38. Crider AM, Witt KA. Somatostatin sst4 ligands: chemistry and pharmacology. Mini Rev Med Chem 2007; 7 (3): 213–20.

(Editor Lu Renmin)

nonpeptide somatostatin analogs: recent advances in its application and research

Documents

structure of peptide

peptide somatostatin

variety of peptide analogs

socalled peptide somatostatin

peptide analogs octreotide

somatostatin sst acts

peptide analog tt

mer sst