Novel phenylamino acetamide derivatives as potent and selective kappa opioid receptor agonists

A novel series of phenylamino acetamide derivatives was synthesized. These amides were shown to be potent and selective kappa opioid receptor agonists.     

Amino acid conjugates as kappa opioid receptor agonists

A novel series of kappa (kappa) opioid receptor agonists were synthesized by incorporating the key structural features of known kappa opioid agonists while replacing the aryl acetamide portion with substituted amino acid conjugates. Compounds 3j (Ki = 6.7 nM), 3k (Ki = 3.6 nM), 3l (Ki = 4.6 nM), 3m (Ki = 0.83 nM) and 3o (Ki = 2 nM) possessed potent affinities for the kappa opioid receptor in vitro with reasonable selectivity over other opioid receptors.     

Arylacetamides as peripherally restricted kappa opioid receptor agonists

Analogues of the kappa (kappa) opioid receptor agonist, ICI 199441, were prepared. Ki values for these analogues at the cloned human kappa opioid receptor ranged from 0.058 to 25 nM. Trifluoromethylaryl derivatives were potent analgesics when administered subcutaneously in the rat and were more peripherally restricted than the parent compound, ICI 199441.     

Novel pyridine derivatives as potent and selective CB2 cannabinoid receptor agonists

Replacement of the phenyl ring in our previous (morpholinomethyl)aniline carboxamide cannabinoid receptor ligands with a pyridine ring led to the discovery of a novel chemical series of CB₂ ligands. Compound 3, that is, 2,2-dimethyl-N-(5-methyl-4-(morpholinomethyl)pyridin-2-yl)butanamide was identified as a potent and selective CB₂ agonist exhibiting in vivo efficacy after oral administration in a rat model of neuropathic pain.     

Identification of potent phenyl imidazoles as opioid receptor agonists

Using previously reported opioid receptor (OR) agonist analogs 4a-c as starting points, the structure-activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs 4h and 4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds 4x and 4y.     

3-Aryl pyridone derivatives. Potent and selective kappa opioid receptor agonists.

A new series of 3-aryl pyridone based kappa opioid receptor agonists was designed and synthesised, based on an understanding of the classical kappa opioid receptor pharmacophore. The most potent of the new compounds were comparable to U-69,593 in receptor affinity, selectivity and functional agonist effect at the cloned human kappa opioid receptor.     

Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities

We recently reported oxazatricyclodecane derivatives 1 as δ opioid receptor (DOR) agonists having a novel chemotype, but their DOR agonistic activities were relatively low. Based on the working hypothesis that the dioxamethylene moiety in 1 may be an accessory site and that it may interfere with the sufficient conformational change of the receptor required for exerting the full agonistic responses, we designed and synthesized new oxazatricyclodecane derivatives 2–4 lacking the dioxamethylene moiety. As we expected, the designed compounds 2–4 showed pronouncedly improved agonistic activities for the DOR. Compound 2a with the 17-cyclopropylmethyl substituent was a potent agonist with the highest selectivity for the DOR and was expected to be a lead compound for novel and selective DOR agonists.     

Discovery of novel pyrimidine and malonamide derivatives as TGR5 agonists

Takeda G-protein-coupled receptor 5 (TGR5) is a promising molecular target for metabolic diseases. A series of 4-(2,5-dichlorophenoxy)pyrimidine and cyclopropylmalonamide derivatives were synthesized as potent agonists of TGR5 based on a bioisosteric replacement strategy. Several compounds exhibited improved potency, compared to a reference compound with a pyridine scaffold. The pharmacokinetic profile of the representative compound 18 was considered moderate.     

Semisynthetic neoclerodanes as kappa opioid receptor probes

Modification of the furan ring of salvinorin A (1), the main active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. Conversion of the furan ring to an aldehyde at the C-12 position (5) has allowed for the synthesis of analogues with new carbon-carbon bonds at that position. Previous methods for forming these bonds, such as Grignard and Stille conditions, have met with limited success. We report a palladium catalyzed Liebeskind-Srogl cross-coupling reaction of a thioester and a boronic acid that occurs at neutral pH and ambient temperature to produce ketone analogs at C-12. To the best of our knowledge, this is the first reported usage of the Liebeskind-Srogl reaction to diversify a natural product scaffold. We also describe a one-step protocol for the conversion of 1 to 12-epi-1 (3) through microwave irradiation. Previously, this synthetically challenging process has required multiple steps. Additionally, we report in this study that alkene 9 and aromatic analogues 12, 19, 23, 25, and 26 were discovered to retain affinity and selectivity at kappa opioid receptors (KOP). Finally, we report that the furan-2-yl analog of 1 (31) has similar affinity to 1. Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors.     

Sulfonamide derivatives as new potent and selective CB2 cannabinoid receptor agonists

A novel series of sulfonamide derivatives 3, the CB(2) receptor agonists, was synthesized and evaluated for activity against the human CB(2) receptor. We first identified sulfonamide 3a, which was obtained by random screening of our in-house chemical library as a moderately active (CB(2) IC(50)=340nM) CB(2) receptor agonist. We then attempted to test its analogues to identify compounds with a high affinity for the CB(2) receptor. One of these, compound 3f, exhibited high affinity for the human CB(2) receptor (IC(50)=16nM) and high selectivity for CB(2) over CB(1) (CB(1) IC(50)/CB(2)IC(50)=106), and behaved as a full CB(2) receptor agonist in the [(35)S]GTPgammaS binding assay (CB(2) EC(50)=7.2nM, E(max)=100%).     

Novel substituted tetrahydrotriazaacenaphthylene derivatives as potent CRF1 receptor antagonists

Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.     

Novel and potent small-molecule urotensin II receptor agonists

A series of analogs of the non-peptidic urotensin II receptor agonist N-[1-(4-chlorophenyl)-3-(dimethylamino)propyl]-4-phenylbenzamide (FL104) has been synthesized and evaluated pharmacologically. The enantiomers of the two most potent racemic analogues were obtained from the corresponding diastereomeric mandelic amides. In agreement with previously observed SAR, most of the agonist potency resided in the (S) enantiomers. The most potent UII receptor agonist in the new series was (S)-N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide (EC₅₀ = 23 nM at the urotensin II receptor).     

Mixed kappa agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan

A series of new N-substituted derivatives of morphinan was synthesized and their binding affinity for the three opioid receptors (mu, delta, and kappa) was determined. A paradoxical effect of N-propargyl (MCL-117) and N-(3-iodoprop-(2E)-enyl) (MCL-118) substituents on the binding affinities for the mu and kappa opioid receptors was observed. All of these novel derivatives showed a preference for the mu and kappa versus delta binding.     

Peptide E and other proenkephalin-derived peptides are potent kappa opiate receptor agonists

Various proenkephalin-derived peptides such as peptide E and the bovine adrenal medulla peptides BAM-12P and BAM-22P are potent competitors on mu and kappa binding sites in guinea pig brain sections. Moreover, they are all potent agonists in the rabbit vas deferens, a specific kappa opiate receptor bioassay. As described before, dynorphin and some of its fragments are also potent kappa agonists. Our results suggest that not only prodynorphin-derived peptides could act as endogenous kappa ligands but also some proenkephalin-derived peptides such as peptide E.     

Novel 5-nitropyrimidine derivatives bearing endo-azabicyclic alcohols/amines as potent GPR119 agonists

A series of GPR119 agonists based on a 5-nitropyrimidine scaffold bearing endo-azabicyclic substituents were synthesized and evaluated for their GPR119 agonistic activities. Most compounds exhibited much stronger EC₅₀ values than that of oleoylethanolamide (OEA). Among them, derivatives from endo-azabicyclic alcohols displayed more potent GPR119 agonistic activities than compounds with endo-azabicyclic amines. Especially the optimized compounds (6, 7, 8, 12, 17) were shown to have potent biological activities and were identified as full agonists. Isopropyl carbamate compound 8 synthesized from endo-azabicyclic alcohol was observed to have the best EC₅₀ value (0.6 nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity.     

Tetrahydroquinoline derivatives as opioid receptor antagonists

Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58 nM (K_i) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications.     

5-Alkyltryptamine derivatives as highly selective and potent 5-HT1D receptor agonists

A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.     

2-Phenylhydroxypropynyladenosine derivatives as high potent agonists at A2B adenosine receptor subtype

Adenosine derivatives bearing in 2-position the (R,S)-phenylhydroxypropynyl chain were evaluated for their potency at human A2B adenosine receptor, stably transfected on CHO cells, on the basis that (R,S)-2-phenylhydroxy-propynyl-5'-N-ethylcarboxyamidoadenosine [(R,S)-PHPNECA] was found to be a good agonist at the A2B receptor subtype. Biological studies demonstrated that the presence of small alkyl groups in N6-position of these molecules are well tolerated, whereas large groups abolished A2B potency. On the other hand, the presence of an ethyl group in the 4'-carboxamido function seems to be optimal, the (S)-PHPNECA resulting the most potent agonist at A2B receptor reported so far.     

Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists

We report the first comprehensive structure–activity study of calindol (4, (R)-N-[(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7-nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC₅₀ of 20 nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.     

Potent and highly selective kappa opioid receptor agonists incorporating chroman- and 2,3-dihydrobenzofuran-based constraints

Two novel chemical classes of kappa opioid receptor agonists, chroman-2-carboxamide derivatives and 2,3-dihydrobenzofuran-2-carboxamide derivatives, were synthesized. These agents exhibited high and selective affinity for the kappa opioid receptor.