Diane L. DeHaven-Hudkins

Potent, Orally Bioavailable Delta Opioid Receptor Agonists for the Treatment of Pain : Discovery of N,N-Diethyl-4-(5-hydroxyspiro-[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)

Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.

Spirocyclic Delta Opioid Receptor Agonists for the Treatment of Pain: Discovery of N,N-Diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) Benzamide (ADL5747)

Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

Caramiphen, iodocaramiphen and nitrocaramiphen are potent, competitive, muscarinic M1 receptor-selective agents

Caramiphen, iodocaramiphen and nitrocaramiphen were examined for affinity at the muscarinic M1, M2 and M3 receptor subtypes in radioligand binding assays. Caramiphen binds with high affinity at the M1 site labeled by [3H]pirenzepine in rat cortex (Ki = 1.2 nM) and displays a 27-fold greater preference for the M1 than the M2 site labeled by [3H](-)-quinuclidinyl benzilate in rat heart, and a 6-fold greater preference for the M1 than the M3 site labeled by [3H]N-methylscopolamine in rat submaxillary gland. Iodocaramiphen binds with high affinity (Ki = 2.1 nM) and selectivity (59-fold) for the M1 vs. M2 subtype, and is 4-fold more selective for the M1 vs. M3 site. Nitrocaramiphen binds with high affinity for M1 sites (Ki = 5.5 nM) and with a 71-fold selectivity over M2, and a 10-fold selectivity for the M1 over the M3 subtype. All three compounds interacted with the M1 binding site in a competitive manner. Nitrocaramiphen and iodocaramiphen are as potent and showed a comparable selectivity for binding to the M1 over the M2 site than the prototypical agent pirenzepine (M1; Ki = 5.2 nM, 51-fold selectivity). Additionally, nitrocaramiphen demonstrates at least a 10-fold selectivity for the M1 over the M3 site. These ester-type antimuscarinics may be better ligands for the study of M1 receptors in brain than the hydrophilic agent pirenzepine.

Design of dual acting anticonvulsant-antimuscarinic succinimide and hydantoin derivatives

Abstract A series of 4-dialkylamino-2-butynyl-succinimide and -hydantoin derivatives were designed containing pharmacophoric elements for dual acting anticonvulsant and antimuscarinic activity. Potent anticonvulsant agents were identified with an extremely rapid onset of protective activity. Succinimides 13 and 13 exhibited ED50 values of 20 and 9.6 mg/kg 10 minutes after administration in the MES seizure model and also exhibited good binding affinity for the M1 muscarinic receptor.

Anticonvulsant activity of caramiphen analogs

Caramiphen potently blocks maximal electroshock (MES)-induced seizures in mice and rats. The anticonvulsant mechanism has been hypothesized to be due to high-affinity binding to sigma recognition sites in brain. To study the structure-activity relationship for anticonvulsant activity of caramiphen we evaluated 8 analogs in MES-induced seizures in rats and also determined whether a correlation exists between anticonvulsant potency and sigma binding affinity. Some of the analogs potently inhibited sigma binding but were devoid of anticonvulsant activity. Aminocaramiphen 2 (ED50 = 3.4 mg/kg) and N-methyl-4-piperidinyl 1-phenylcyclopentanecarboxylate 9 (ED50 = 4.8 mg/kg) showed anticonvulsant activity comparable to caramiphen (ED50 = 3.1 mg/kg), although in sigma binding assays the affinities were 3-and 30-fold less than caramiphen, respectively. In the presence of 250 microM of phenytoin, caramiphen and p-aminocaramiphen showed 3- to 5-fold increases in affinity for [3H](+)pentazocine binding, whereas piodocaramiphen, which was inactive as an anticonvulsant, showed no change in affinity for sigma binding. These results indicate that anticonvulsant activity of the caramiphen analogs is not due to interaction with sigma binding sites.

RLH-033, a novel, potent and selective ligand for the σ1 recognition site

RLH-033 [2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)cyclopentanecarboxylate HCl] is a rationally designed ligand that was synthesized and evaluated for its binding affinities at σ1 and σ2 sites in guinea pig brain. RLH-033 has high affinity (Ki = 50 pM) for σ1 sites labeled by [3H](+)-pentazocine, while it has over 2000-fold less affinity at σ2 sites labeled by [3H]1,3-di(2-tolyl)guanidine (DTG) in the presence of 500 nM (+)-pentazocine (Ki = 105 nM). Unlike its potent σ activity, the compound has little affinity for dopamine D1 (Ki = 2.9 μM), D2 (Ki = 2.35 μM), muscarinic M1 (Ki = 0.88 μM) or M2 (Ki = 1.7 μM) receptors, and none at all for N-methyl-D-aspartate, phencyclidine and opioid receptors. Thus, RLH-033 is the most potent σ1 ligand reported to date, and its very high affinity suggests it may be a useful radioligand to characterize the pharmacology of σ1 recognition sites.

Phenytoin derivatives as potent σ ligands

Abstract A series of 4-phenylpiperidinyl and 4-phenylpiperazinyl alkyl spaced 5,5-diphenylhydantoins was prepared and evaluated for affinity at σ sites. Increasing the alkyl spacer between the two pharmacophore recognition units resulted in a progressive increase in σ binding affinity. The pentyl 12 and hexyl 13 4-phenylpiperdine derivatives exhibited subnanomolar affinity (0.7 nM and 0.6 nM) for the PENT site.

Synthesis and binding affinity of 2,3,3a,4,9,9a-hexahydro-9,4-(iminomethano)-1H-benz[f]indenes. Ligands for the PCP site of the NMDA receptor

A series of 2,3,3a,4,9,9a-hexahydro-9,4-(iminomethano)-1H-benz[f]indenes was prepared and their ability to displace [3H]TCP was measured. The 5-amino derivatives 5 and 12b were the most potent members of this series with Ki values of 14 nM and 8 nM respectively. The orientation of the cyclopentane ring was crucial for binding potency, with the endo isomer 12a >10 times more potent than the exo-isomer 13.