α₂ Adrenoceptor Agonists as Potential Analgesic Agents. 2. Discovery of 4-(4-Imidazo)-1,3-dimethyl-6,7-dihydrothianaphthene as a High-Affinity Ligand for the α_2D Adrenergic Receptor

Abstract

Pages 765-768. Due to an error at the final stage of transferring the ASAP web version (published February 17, 2000) to the printed version, Scheme 4 and Tables 1 and 2 were inadvertently deleted. Unfortunately consideration of this data is essential for interpreting the other parts of the published paper; therefore, the communication is printed here in its entirety. Received November 15, 1999 Introduction. The treatment of pain continues to be the subject of considerable pharmaceutical and clinical research. 1 R 2 Adrenoceptor agonists are intriguing because they produce clinically effective analgesia that is devoid of opioid-related side effects. 2 The R 2 adrenergic agonist clonidine (1) is prescribed for the epidural treatment of severe pain, and the R 2 agonist dexmedetomidine (2) is used in veterinary practice and for humans in several countries outside the United States. 3 The primary site of antinociceptive action for R 2 adrenergic analgesia is in the dorsal horn of the spinal cord. 2a R 2 Adrenergic receptors are localized largely in the presynaptic membrane, and activation of these receptors inhibits the release of pain-inducing neurotransmitters such as substance P, glutamic acid, and CGRP. We have recently reported the potent R 2 adrenergic receptor affinity and analgesic activity associated with (imidazomethyl)oxazoles and -thiazoles, such as 3 . 4 In addition, we have investigated a large number of (imidazomethyl)thiophenes, such as 4, that have a similar biological profile. 5 Analyzing the preferred conformations of 4 by molecular modeling revealed significant torsional freedom for rotation of the two single bonds between the imidazole and thiophene. To restrict the rotation of this molecule, we extended and combined the 2-ethyl substituent with the bridging carbon atom to obtain the (imidazo)thianaphthene chemical series (e.g. 8 and 9, Scheme 1). These compounds are potent R 2 adrenergic receptor ligands, and certain members of the series are very active in animal models of antinociception. 4-(4-Imidazo)-6,7-dihydrothianaphthene (14) has a favorable biological profile in vivo and is a prototype for this class of analgesic agents.Chemistry. Several complementary methods were used to prepare the (imidazo)thianaphthenes. Reaction of thienyl ketone 5 6 with the Grignard reagent 7 derived from 4-iodo-1-tritylimidazole (6) gave alcohol 7 (84%; Scheme 1). This material was either treated with HCl in MeOH to yield unsaturated derivative 8 (20%) or reduced to fully saturated 9 by hydrogenation over palladium on carbon (29%). Although this method was used for the preparation of 14 and 15, we also developed a strategy involving vinyl triflate coupling as shown in Scheme 2. Thienyl ketone 10 was converted to vinyl triflate 11 in 90% yield by using triflic anhydride and a hindered pyridine base. Coupling of either the 4-imidazo zinc reagent 12 or the 4-(tributylstannyl)imidazole (not shown) gave alkene 13 (78% when using zincate 12). 8 * To whom correspondence should be addressed: Allen B. Reitz. M...

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

“…A new class of α 2 -AR agents is represented by the (imidazo)thianaphthene derivatives, among which compound 90 is the most potent for α 2D (K i = 0.0086 nM) and 10,000-fold selective with respect to α 1 -ARs [167].…”

“…Another example is represented by the couple 90 and 124, belonging to a series of conformationally constrained imidazole analogs, prepared as potential analgesic agents [167]. Whereas 124 shows a modest α 2 -AR binding affinity and antinociceptive activity, 90 has a high affinity value but is devoid of antinociceptive activity.…”

α2-Adrenergic agonists as analgesic agents

“…In clinical trials, 12 was as ef fective as propofol/morphine or midazolam/morphine in providing patient comfort. Compound 15 was extremely potent at the α 2 -adrenoceptor with a K i of 0.0086 nM and showed some modest activity in the MAIT paradigm [25].…”

“…No biological data are given for any of the compounds presented. In five closely related patents, Procter & Gamble disclosed series of indoles (24) [115], benzoxazoles (25) [116], benzthiazoles (26) [117] and benzimidazoles (27 and 28) [118,119]. Again, there is no biological data given for any of the compounds which are described.…”

α2 Adrenoceptor Agonists as Potential Analgesic Agents. 3. Imidazolylmethylthiophenes

“…In two previous communications we have described the synthesis and pharmacological profile of a series of imidazolylmethylthiazoles and -oxazoles 4 and imidazolyldihydrothianaphthenes 5 as potent R 2 agonists. One active compound from the imidazolylmethylthiazole series was RWJ 37210 (2), which showed good binding at the R 2D adrenergic receptor (K i ) 18 nM) and was a potent antinociceptive agent with an ED 50 ) 1.8 mg/kg po in the mouse abdominal irritant test (MAIT).…”