NK1 receptor antagonist
An example of a drug in this class is
The first registered clinical use of NK1 receptor antagonists was the treatment of emesis, associated with cancer chemotherapy.[6]
History
In 1931, von Euler and Gaddum discovered
The neurokinin-1 receptor
Tachykinins are a family of
Tachykinin NK1 receptor, often referred to as NK1 receptor, is a member of family 1 (
Drug discovery and development
In 1991, three different groups researched different NK1 receptor antagonists by
Rhône-Poulenc discovered the compound RP-67580, which has high affinity for the NK1 receptor in rats and mice, but not in humans. SAR studies that were performed in order to improve the selectivity for the human NK1 receptor resulted in the development of a compound called RPR-100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraines but then terminated, as was the case with other NK1 receptor antagonists that were tested for the same indication.[12][17]
The third company, Pfizer, discovered a benzylamino quinuclidine structure, which was called CP-96345 (figure 1). CP-96345 has a rather simple structure, composed of a rigid quinuclidine scaffold containing a basic nitrogen atom, a benzhydril moiety and an o-methoxy-benzylamine group. This compound showed high affinity for the NK1 receptor, but it also interacted with Ca2+ binding sites. Strongly basic quinuclidine nitrogen on the compound was considered to be responsible for this Ca2+ binding, which caused a number of systemic effects, unrelated to the blocking of the NK1 receptor. For that reason and also to simplify the structure, alkylation at this site was performed to produce analogs.
The compound CP-99994 was synthesized by replacing the
Development of the first drug
In 1993,
of CP-99994 compound. To improve oral bioavailability, the piperidine nitrogen was functionalized in order to reduce its basic nature. The group that gave the best effects on basicity was 3-oxo-1,2,4-triazol-5-yl moiety and it gave compounds such as L-741671 and L-742694. AOther compounds
Many compounds have been described by various pharmaceutical companies besides the compounds that led to the discovery of aprepitant. GR-205171 (figure 4) was developed by
LY-303870, or
By a general hypothesis on peptideric
Binding
There is more than one ligand binding domain on the NK1 receptor for the non-peptide antagonists, and these binding domains can be found in various places. The main ligand binding site is in the hydrophobic core between the loops and the outer segments of transmembrane domains 3–7 (TM3–TM7).[16] Several residues, such as Gln165 (TM4), His197 (TM5), His265 (TM6) and Tyr287 (TM7) are involved in the binding of many non-peptide antagonists of the NK1 receptors.[7][16] It has been stated that Ala-replacement of His197 decreases the binding affinity of CP-96345 for the NK1 receptor. His197 interacts with the benzhydryl moiety of CP-96345. Experiments have showed that replacing Val116 (TM3) and Ile290 (TM7) decreases the binding affinity of CP-96345. Evidence indicates that these residues probably do not interact with antagonists, but would rather indirectly influence the overall conformation of the antagonist binding site. The residue Gln165 (TM4) has also proven to be meaningful for the binding of several non-peptide antagonists, possibly through the formation of a hydrogen bond.[17][19] Phe268 and Tyr287 have been proposed as possible contact points for both agonist and antagonist binding domains.[16]
The significance of His265 has been confirmed in the binding of antagonists to NK1 receptor. His265 interacts favorably with the 3,5-bis-trifluoromethylphenyl group (TFMP group) of an analog CP-96345. Nonetheless, it has been demonstrated that Ala-replacement of His265 does not affect the binding affinity of CP-96345.[11]
Some other residues that are thought to be involved in the binding of non-peptide antagonists to NK1 receptor are Ser169, Glu193, Lys194, Phe264, Phe267, Pro271 and Tyr272. Each structural class of non-peptide NK1 receptor antagonists appears to interact with a specific set of residues within the common binding pocket.[7][16]
Structure-activity relationship (SAR) and pharmacophore
There are at least three essential elements which are important for the interactivity of a ligand with the NK1 receptor. First, the ion-pair site interactivity with the bridgehead nitrogen; second, the accessory binding site interactivity with the benzhydryl group; and third, the specific site interactivity with the (2-methoxybenzyl) amino side chain. Studies have shown that compounds with piperidine ring have selectivity for NK1 receptor over NK2, NK3, opioid and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine, a selective NK1 receptor antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK1 receptor antagonists.[15] The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site.[20] It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.[15]
In the development of MK-869, it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the TFMP group appeared to be especially important, and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group, can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.[11] The presence of an intramolecular face-to-face π–π interaction between two
Future development
Chemotherapy-induced
The NK2 and NK3 receptors are also targets for novel classes of medications, and also show prominent antidepressive and anxiolytic effects.[21] Studies showed that the inhibition constant (Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors. The affinity was also much lower for NK2 and NK3 receptors.[5] Since
See also
- Casopitant
- Maropitant
- Rolapitant
- Tachykinin receptor
- G protein-coupled receptors
References
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