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

www.elsevier.com/locate/jmcpla

Nonpeptide somatostatin analogs: recent advances in its application and research Wang Song1, Liang Qingmo1*, Liao Duanfang2 1

Department of Oncological Surgery, Nanhua Hospital, University of South China, Hengyang 421002, Hunan, China

2

Institute 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

* Corresponding author. Tel.: 86-734-83580861; Fax: 86-734-83583991 E-mail address: hylqm@vip.sina.com (Liang Q.)

(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


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

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 somato- statin (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

365

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. Using 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-dibutyl3-(4-benzene-4-yl-1H-imidazol-2-yl)-2,3,4,9-tetrah ydro-1H-ȕ-carboline and BN81674 is (3R)-1, 1-Diamyl-3-(4-benzene-4-yl-1H-imidazol-2-yl)-2, 3,4,9-tetrahydro-1H-ȕ-carboline; In patent US 6221870, SRA880 chemical structure is [3R, 4aR,10aR]-1,2,3,4,4a,5,10,10a-octahydro-6-metho xy-1-methyl-benz[g]-quinoline-3-carboxylic-acid-4 -(4-nitro-phenyl)-piperazine-amide, hydrogen malonate; and, for patent US 6159941, NNC 26-9100 chemical structure is 1-(3-(N-(5-Bromo-pyridin-2yl)-N-(3,4-dichlorobenzyl)amino)propyl)-3-(3-(1Himidazol-4-yl)propyl)thiourea.

3. Pharmacological studies 3.1. Ligand-binding assays The basic principle of ligand-binding studies


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OH

HN

H N

O O

H2N

N H

NH NH

O

HO

HN

H N

Molecular modeling

O

H N

H2N

OO

Database search

N

NH

O

O L-264,930

L-363,377 H

H2N

H N

H2N

NH

O

N

L-797,591

H2N

H N

NH O

N

L-779,976

NH

F

H N O

OO

H N

H2N

H N

N OO

N

H 3 CO N

NH N H

N H NO 2

NH L-796,778 H N

H2N

F

O OO

O

O N H

O

OO

NH

NH 2

L-803,087

L-817,818

Fig. 1. Color-coding of SST receptor-selective compounds illustrates the relationship of various parts of each molecule 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] .

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-Tyr 11-SRIF and 125 I-Tyr 3 octreotide, for example. In the presence or absence of nonpeptide somatostatin, after repeatedly clearing the 125I-Tyr 11-SRIF and

125

I-Tyr 3 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 accumulation

of

forskolin-stimulated

cAMP

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


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Table 1 Patents published for non-peptide SST analogs from 2000 to 2007

No.

USPTO Patent/ USPTO Published Application

Core structure Formula

1

B

US20030191134

R3

1

N 3 2

2003 A

N

or

R2

US20040019092

B R3

R4

Z1

R5

hydantoin

SSTR2 2004

R1 N 4 3 5 1 2 N

6

US7189856 [2–4]

Date of Patent

R1 4 5

R4

Selective SSTR

Z2

R2

2007

Z3 R5

2

US 6387932 [5]

( )q

H N

R1

Z

N

B

A

( )r

Y

R 88

í

SSTR2

2002

ȕ-carboline

SSTR3

2005

4,1-benzoxazepines

SSTR5

2002

O O N

R3

R4

3

R1

R5

US 6861430 [6]

N

NH NH

R4

R2 R3

N H

4 L

R2

B Y

US 6352982 [7] A

D N R1

X

E G

Z


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

Table 1 (Continued) No.

USPTO Patent/ USPTO Published Application

Core structure Formula

5 O

N

R5 R6

N R3 H

N

R1

Date of Patent

R4

N

US 6221870 [8]

Selective SSTR

2001

R2

ergoline

SSTR1

O N O

SRA880 [9] O (ˉ) CH 3 O6

H

N N 38 H 1 N CH 3

COOH

2004

COOH

9

6

X A

US6159941 [10]

B A B

(CH 2 )

N

(CH 2 ) n

N

N

R1

R2

(CH 2 ) p

X indicates S (thiourea) or NH (guanidine)

D

S R2 (CH 2 )

N

N

N

(CH 2 ) p

SSTR4

2000

SSTR1 SSTR4

2007

D

R1

(CH 2 ) n

7 R2 O

US20070129313 [11] N

Sulfonylation

O N S

N

O

B

O

R1

8 R

US20070129422 [12]

O Q

N R

N

B

SSTR1

R2 n

B

Sulfonylation

2007

A K

O

N

R3

S

O

D

SSTR4


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

Table 1 (Continued) No.

USPTO Patent/ USPTO Published Application

Core structure

Selective SSTR

Date of Patent

imidazole

SSTR1– SSTR5

2003

imidazole

SSTR1– SSTR5

2007

Pyrido-thieno-dia zepines

SSTR1– SSTR5

2006

Pyrido-thieno-dia zepines

SSTR1– SSTR5

2004

Formula

9

a-(Y) n

N

R1 N

R2

R3

N (CH 2 ) m b-(Z) n

R4 R

US6602849 [13]

5

or

O X4

(Y) a

X3 X

N

R1 N

R2

R3

N (CH 2 ) m

2

X1

R4

R5

(Z) n O

10

R3 R4

US 7238695 [14]

R

R5

N

N 2

R1

N

R6

11

R1

US 7015213 [15]

N W N

S

N N

R3

12

R 2a R 2b

N

R2 A

US 6777408 [16]

R1

N

S

B

R 3a R 3b

N R4

X

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


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Table 2 Ligand-binding assays of non-peptide SST analogs No.

USPTO Patent/

Affinity and quantity to the SSTRs

USPTO Published Application 1

US20030191134 SSTR2: IC 50 =0.1–1×10 6 nmol/L

US20040019092 US7189856 [2–4] 2

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

SSTR3: K i =0.64 nmol/L SSTR3: K i =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: K i =6 nmol/L

6

US20070129313 [11] : Compounds 2

SSTR1: K i =34±14 nmol/L

Compounds 5

SSTR4: K i =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.

and the IC50 and ED 50 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 3 Inhibition of forskolin-stimulated cAMP accumulation of non-peptide SST analogs NO.

USPTO Patent/

Antagonist/agonist to the SSTRs

USPTO Published Application 1

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

SSTR3: IC50 = 0.84 nmol/L

antagonist

SSTR3: IC50 = 2.7 nmol/L

antagonist

SSTR5: ED50 = 0.3 nmol/L

antagonist

2

US 6352982 [7]˖compounds 102

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

compounds 5


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

200

Control

175

Compound

371

4.1. SSTR2-selective non-peptide SST analogs

hGH%

150 125 100 75 50 25 0

1 -1

0

10 1

2 3 Time (h)

100 ȝg/kg s.c. 4

5

6

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

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.

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 Į cells, which expressed SSTR2, whereas insulin secretion from ȕ 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


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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 RFE011, 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 immunostaining to show that SSTR5 was expressed exclusively in the ȕ cells of rat pancreatic islets and mediated insulin secretion, while the SSTR2A had been localized to rat pancreatic Į 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 differentergic 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 hyperactivity disorders), bipolar disorders and schizophrenia.


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

4.4. SSTR1-, SSTR4- and SSTR1/4-selective nonpeptide 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

373

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 US6777408) 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: Anticancer 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


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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, betaglucosides, 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.

2. Shapiro G, Natchus MG, Lockwood MAˈJurczyk 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 MAˈJurczyk 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.

ȕ-carboline

derivatives

and

its

pharmaceutical use against depression and anxiety. US patent 6861430. 2005 March 1. 7. Mabuchi H, Suzuki N, Miki T, inventors. 4,1benzoxazepines, 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

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(Editor Lu Renmin)


Nonpeptide somatostatin analogs: recent advances in its application and research