Corticotropin-Releasing Factor Receptors

Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The cloning of multiple receptors for CRF, identification of additional endogenous ligands, as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study.

There are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1, CRF2 receptors (belonging to the superfamily of G protein-coupled receptors) and the CRF-binding protein. The CRF2 receptor exists as three splice variants of the same gene that have now been designated CRF2(a), CRF2(b) and CRF2(c) as per IUPHAR nomenclature. The pharmacology and localization of these proteins in brain and periphery has been well established. In brain, the CRF1 receptor is localized primarily to cortical and cerebellar regions while the CRF2(a) receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. Peripherally, the CRF1 receptor is localized in the gut and uterus while the CRF2(b) receptor is primarily localized to heart, skeletal muscle and to cerebral arterioles and choroid plexus. The CRF2(c) receptor has been identified in human amygdala.

The natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF1 receptor subtype, with lower affinity for the CRF2 receptor family making them good labels for the CRF1 receptor. On the other hand, the non-mammalian ligand [125I]-sauvagine and synthetic [125I]-antisauvagine-30 have been characterized as high affinity ligands for the CRF2 receptor. These radioligands have become useful tools in the discovery of non-peptide, high affinity, and selective receptor antagonists. The discovery of urocortin 2, and urocortin 3, endogenous mammalian peptides that have high affinity for the CRF2 receptor and very low affinity for the CRF1 receptor, has offered new insights into the role and function of this receptor subtype.

Non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have been a major focus of discovery research. Compounds such as CP 154,526, NBI 27914, antalarmin, DMP 696, NBI 30775/R121919 and many others have all demonstrated in vitro inhibition of CRF-induced second messenger or other functional effects. In addition, when administered peripherally, these compounds compete for ex vivo [125I]-sauvagine binding to CRF1 receptors in brain sections demonstrating their ability to cross the blood brain barrier. In in vivo studies, peripheral administration of these compounds attenuates CRF or stress-induced behavioral changes, elevations in plasma ACTH levels, seizure activity or colonic motility. Furthermore, in a preliminary clinical phase IIA study, the CRF1 receptor antagonist NBI 30775/R121919 was found to have activity in patients with Major Depressive Disorder.

Although the primary focus for CRF1 receptor selective antagonists is still in the area of anxiety and depression, different animal models have demonstrated a beneficial effect of these molecules in the neurodegeneration associated with stroke, the pain associated with various inflammatory responses and a potential utility in GI disorders such as irritable bowel syndrome. Although selective high-affinity non-peptide small molecules have not yet been identified for the CRF2 receptor subtype, the potential indications for such molecules range from eating disorders to cerebrovascular disease, migraine and congestive heart failure. It is also tempting to speculate that as more information becomes available through the drug discovery efforts of both the pharmaceutical industry and academic research, the interaction between the various receptor subtypes may play a further unique role in the etiology of various disease states.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Namea CRF1 (human, rat, mouse) CRF2(a)
Alternate Name(s) CRF-RA (human, rat)
PC-CRF (rat, mouse)
CRF (human, rat)
Structural Information 415 aa (rat)
415 aa (human)
415 aa (mouse)
411 aa (rat)
411 aa (human)
Agonistsb CRF (C3042)
UCN1 (U4127 (h), U6631 (r))
CRF (C3042)
UCN1 (U4127 (h), U6631 (r))
UCN2 (U9507 (m))
UCN3 (U1008 (h))  
Peptide Rank Order of Potencies Sauvagine (S3884) =
Urotensin I (U7253) =
UCN1 (U4127 (h), U6631 (r)) =
oCRF (C3167) =
r/hCRF (C3042) =
bCRF (C2671) >
Astressin (A4933) >
D-Phe r/hCRF(12-41) >
α-helical oCRF(9-41) (C2917) >>
UCN2 (U9507) (m)
Astressin 2B (A5227)
r/hCRF(6-33) (C0961)
r/hCRF(9-33)
r/hCRF(1-41)OH
VIP (V6130)
AVP (V9879, V0377)
Sauvagine (S3884) =
Urotensin I (U7253) =
UCN1 (U4127 (h), U6631 (r)) =
UCN2 (U9507 (m)) =
UCN3 (U1008) =
Astressin 2B (A5227) >
r/hCRF (C3042) >
oCRF (C3167) >
bCRF (C2671) >
D-Phe r/hCRF(12-41) >
α-helical oCRF(9-41) (C2917) >>
r/hCRF(6-33) (C0961)
r/hCRF(9-33)
r/hCRF(1-41)OH
VIP (V6130)
AVP (V9879, V0377)
Antagonistsc α-helical oCRF(9-41) (C2917)
D-Phe r/hCRF(12-41)
Astressin (A4933)
α-helical oCRF(9-41) (C2917)
D-Phe r/hCRF(12-41)
Astressin (A4933)
Astressin-2B (A5227)
Antisauvagine-30 (A4727)
Selective Non-Peptide Antagonists CP 154,526
NBI 27914 (N3911)
Antalarmin (A8727)
CRA 1000
CRA 1001
DMP 696
DMP 904
NBI 30775/R121919
NBI 35965
Not Known
Signal Transduction Mechanism Gs (increase cAMP) Gs (increase cAMP)
Radioligands of Choice [125I]-Tyr0 oCRF
[125I]-Tyr0 r/hCRF
[125I]-Tyr0 Sauvagine
[3H]-Urocortin
[125I]-Tyr0 Sauvagine
[3H]-Urocortin
[125I]-Antisauvagine-30
Tissue Expression Central nervous system, pituitary, testes, gastrointestinal tract, uterus/placenta Central nervous system, gastrointestinal tractd
Physiological Function Stimulates release of ACTH, regulates response to stress Stimulates release of cAMP, regulates food intake
Disease Relevancee Anxiety, depression, irritable bowel syndrome, parturition Anxiety, eating disorders

 

 

Currently Accepted Namea CRF2(b) CRF2(c) CRF-BP (human
rat)
Alternate Name(s) CRF (human, rat, mouse)
CRF-RB (mouse)
HM-CRF (mouse)
CRF (human)  
Structural Information 431 aa (rat)
431 aa (mouse)
431 aa (human)
397 aa (human) 322 aa (rat)
322 aa (human)
Agonistsb CRF (C3042)
UCN1 (U4127 (h), U6631 (r))
UCN2 (U9507 (m))
UCN3 (U1008 (h))  
CRF (C3042)
UCN1 (U4127 (h), U6631 (r))
UCN2 (U9507 (m))
CRF (C3042)
UCN1 (U4127 (h), U6631 (r))
Peptide Rank Order of Potencies r/hCRF (C3042) =
Sauvagine (S3884) =
Urotensin I (U7253) =
UCN1 (U4127 (h), U6631 (r)) =
UCN2 (U9507 (m)) =
UCN3 (U1008) =
Astressin 2B (A5227) >>
hGRF (G8895)
AVP (V9879, V0377)
UCN1 (U4127 (h), U6631 (r)) =
Urotensin I (U7253) >
α-helical oCRF(9-41) (C2917) >
r/hCRF (C3042)
Urotensin I (U7253) >
r/hCRF (C3042) =
r/hCRF(1-41)OH =
α-helical oCRF(9-41) (C2917) >
r/hCRF(6-33) (C0961) >
r/hCRF(9-33) >
Sauvagine (S3884) >>
D-Phe r/hCRF(12-41) >
oCRF (C3167) =
bCRF (C2671) =
Astressin (A4933)
Antagonistsc α-helical oCRF(9-41) (C2917)
D-Phe r/hCRF(12-41)
Astressin (A4933)
Astressin-2B (A5227)
Antisauvagine-30 (A4727)
α-helical oCRF(9-41) (C2917) Not Known
Selective Non-Peptide Antagonists Not Known
Not Known
Not Known
Signal Transduction Mechanism Gs (increase cAMP) Gs (increase cAMP) Not Known
Radioligands of Choice [125I]-Tyr0 Sauvagine
[3H]-Urocortin
[125I]-Antisauvagine-30
[125I]-Tyr0 Sauvagine
[3H]-Urocortin
[125I]-Antisauvagine-30
[125I]-Tyr0 r/hCRF
[3H]-Urocortin
Tissue Expression Skeletal muscle, heart/vasculature, gastrointestinal tractd, uterus Human amygdala Central nervous system, liver, plasma, placenta, adrenal
Physiological Function Vasodilation, decreases blood pressure, modulates muscle mass Stimulates release of cAMP Reduces CRF activity
Disease Relevancee Cerebrovascular disease, migraine, congestive heart failure, parturition Not Known
Alzheimer’s Disease

 

Footnotes

a) Nomenclature as recommended by the NC-IUPHAR Subcommittee on corticotropin-releasing factor receptors, see Hauger, et. al. 2003.

b) For the CRF2 receptor subtype, the recent identification and cloning of Urocortin 3 adds to this subfamily of ligands representing endogenous mammalian peptides that have over 1000-fold selectivity in affinity and functional activity for the CRF2 receptor over the CRF1 receptor.

c) With the exception of the novel small molecule receptor antagonists being discovered, there are no selective endogenous antagonists for any of these receptor subtypes. Antisauvagine-30 has been reported to have about a 10 - 50-fold selectivity at the CRF2 versus the CRF1 receptor subtype, but this is not an endogenous peptide. No selective non-peptide compounds have appeared to date for any of the CRF2 receptor isoforms or for the CRF binding protein.

d) Both CRF2(a) and CRF2(b) receptors are listed where the physiological function described in the literature makes no mention of the specific isoform and is listed as only the CRF2 receptor.

e) To date there have been no clinical proof-of-concept studies completed that demonstrate a clear disease relevance of either activation or blockade of the CRF system. The disease relevance listed is proposed from preclinical and early clinical studies.

 

Abbreviations

Antalarmin: N-Butyl-N-ethyl-[2,5,6,-trimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine
Antisauvagine-30: (D-Phe11,His12)-Sauvagine, Fragment 11-40
Astressin: [D-Phe12,Nle21,38,Glu30,Lys33]-Corticotrophin releasing factor fragment 12-41
Astressin 2B: Cyclo(31-34)[D-Phe11,His12,C(α)MeLeu13,39,Nle17,Glu31,Lys34]Ac-Sauvagine(8-40)
AVP: Arginine vasopressin<br>
CP 154,526: Butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine
CRF: Corticotrophin releasing factor
CRF-BP: CRF-Binding Protein
r/hCRF: rat/human CRF
oCRF: ovine CRF
bCRF: bovine CRF
r/hCRF(1-41)OH: Deamidated rat/human corticotrophin releasing factor
D-Phe r/hCRF(12-41): [D-Phe12,Nle21,38,Ala32] r/hCRF(12-41)
CRA 1000: 2-(N-(2-Methylthio-4-isopropylphenyl)-N-ethyl-amino-4-(4-(3-fluorophenyl)-1,2,3,6-tetra-hydropyridin-1-yl)-6-methylpyrimidine)
CRA 1001: 2-(N-(2-Bromo-4-isopropylphenyl)-N-ethyl-amino-4-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine)
DMP696: 4-(1,3-Dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)pyrazolo[1,5-a]-1,3,5-triazine
DMP904: 4-(3-Pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine
hGRF: Human Growth hormone releasing factor
NBI 27914: 2-Methyl-4-(N-propyl-N-cyclopropanemethylamino)-5-chloro-6-(2,4,6-trichloroanilino)pyrimidine
NBI 30775/R121919: 3-[6-(Dimethylamino)-4-methyl-3-pyridinyl]-2,5-dimethyl-N,N-dipropylpyrazolo[1,5-a]pyrimidin-7-amine
NBI 35965: (S)-6-Cyclopropylmethyl-2-(2,4-dichloro-phenyl)-7-ethyl-4-methyl-7,8-dihydro-6H-1,3,6,8a-tetraaza-acenaphthylene
UCN1, UCN2, UCN3: Urocortin 1, Urocortin 2 and Urocortin 3.
VIP: Vasoactive intestinal peptide

h: human
o: ovine
m: mouse
r: rat
r/h: rat/human

 

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References