Summary of General PD and PK Features in Groups of Ligands of the Different GPCR Classes and State of Modelling Approaches

Receptors

GPCR Class

Compounds

References

General features

Modelling

References

Neuropeptide Y1

Class A, (peptide receptor)

Y-973

BIBO3304 [1]

BIP3226 [2]

Cmpd. 5 [4]

Cmpd. 23 [5]

BMS 193858 [6]

[50]

[66]

[66]

[66]

[67]

[69]

Selective antagonists with PK drawbacks like high molecular weight, high Pgp ratio or inappropriate log P

Complete crystal structures of NPY receptors yet not available, but interaction at binding pocket of NPY2R investigated

[48]

[65] [67]

Neuropeptide Y2

Class A,

(peptide

receptor)

BII246

JNJ31020028 [7]

CYM9691 [8]

CYM9624 [9]

[65]

[70]

[63]

[63]

Orexin-1

Class A

(peptide receptor)

SB334867 [13]

rac-10 [14]

Cmpds. 47-51 [15] [16]

Cmpd. 54 [17]

Cmps. 24 [18]

SB674042 [21]

[89] [90]

[91]

[91]

[79]

[92]

[94]

Selective antagonists with

PK drawbacks like high molecular weight, high Pgp ratio or inappropriate log P; low density of the receptors in brain tissue

Complete crystal structure available for both receptor subtypes

[48]

Orexin-2

Class A

(peptide

receptor)

2-SORA-DMP [22]

TCSOX229 [23]

Cmpd [24]

Cmpd. 4f [25]

Diazaspiro-cmpds. [26] [27] [28]

CW4 [30]

[94]

[95]

[96] [97]

[97]

[98]

[99]

CX3CR1

(Fractalkine receptor)

Class A

(chemokine receptor)

AZD8797 [37]

FBTTP [41]

[42]

[49]

Functional antagonist with high log P and good p.o. efficacy

Modelling with US28; Fractalkine characterized; crystal structure of the receptor incomplete

[48]

Corticotropin releasing factor

Class B1

(peptide

receptor)

CP316311

CP376395 [42]

BMS6650553 [52]

Phenylaminopyrazinones [44] [45] [46]

Dihydropyridinpyrazonones [47] [48] [49] [50] [51]

[119]

[59]

[122] [123]

[120]

[121]

Rather allosteric binding and pharmacokinetic drawbacks

Complete CRFR1 crystal structure available; first studies with CP376395

[48]

[59]

[60]