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SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.

A series of 5-(pyridine-3-yl)octahydropyrrolo[3,4-c]pyrroles have been prepared that exhibit high affinity to alpha4beta2 and/or alpha7 nicotinic acetylcholine receptors (nAChRs). Simple substitution patterns have been identified that allow construction of ligands that are highly selective for either nAChR subtype. The effects of substitution on subtype selectivity provide some insight into the differences in the ligand binding domains of the alpha4beta2 and alpha7 receptors, especially in regions removed from the cation binding pocket.

Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.

A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB 2 cannabinoid receptor ligands. Two unsubstituted indoles ( 5, 32) were the starting points for an investigation of the effect of indole ring substitutions on CB 2 and CB 1 binding affinities and activity in a CB 2 in vitro functional assay. Indole ring substitutions had varying effects on CB 2 and CB 1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB 2/CB 1 binding selectivity in some cases (i.e., 7- 9, 15- 20). All indoles with the morpholino-ethyl side chain ( 32- 43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs ( 5- 31). Several agonists were active in the complete Freund's adjuvant model of chronic inflammatory thermal hyperalgesia ( 32, 15).

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.

In search of an alpha2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the alpha2-receptor (K(i) = 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the alpha2-receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety of structural modifications to the arylethyl fragment are possible with retention of this dual activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are optimal with alternate substitutions producing compounds retaining high affinity for the alpha2-receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl analogs suggests that the favored orientation of the oxygen lone pairs may be away from the 6-position of the tetralin.

A-80426, (N-[2-(Benzofuran-6-yl)ethyl]-N-[(R)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]-N-methylamine) represents the first example of a new structural class of agents combining potent α-2 antagonist activity with equivalent 5-HT uptake inhibitory activity. This profile of combined activities may have utility in the treatment of depression.

ABT-200, (±)-(1′R*, 3R*)-3-phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylenedioxy-1′-naphthalenyl)methyl]pyrrolidine, ( 1a/b ) represents the first example of a new structural class of potent α-2 antagonists which possess the additional property of norepinephrine (NE) uptake inhibition. This profile of combined activities is expected to have utility in the treatment of depression.

SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.

A-80426, (N-[2-(Benzofuran-6-yl)ethyl]-N-[(R)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl-methyl]-N-methylamine) represents the first example of a new structural class of agents combining potent α-2 antagonist activity with equivalent 5-HT uptake inhibitory activity. This profile of combined activities may have utility in the treatment of depression.

Several 3-acylindoles with high affinity for the CB(2) cannabinoid receptor and selectivity over the CB(1) receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB(2) agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB(2) receptor. A study of N1 nonaromatic side chain variants provided potent agonists at the CB(2) receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB(2) receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB(2) receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB(2) functional assay than were nonaromatic side chain analogues.

A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.

In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).

A series of esters of adenosine-5'-carboxylic acid has been prepared. Most of the compounds were nontoxic, causing prolonged increases in coronary sinus PO2 when administered to anesthetized dogs; the ethyl ester was most active. Nitrosation and oxidation of the ethyl ester 12 gave respectively inactive inosine ethyl ester 30 and the fairly active N1-oxide ethyl ester 29.

The formation of 3-oxo-3,4-dihydro-2H-1,4-benzothiazine (IIIa) by cyclization of alkyl 2-haloacetamidophenyl sulfides (I) was investigated; it is proposed that the reaction proceeds via a six-membered sulfonium halide. The preparation of 4-alkyl derivatives of IIIa and of 4-alkyl and 4-acyl derivatives of its reduction product 3,4-dihydro-2H-1,4-benzothiazine (Va) is described. Acylation of Va was shown to proceed without opening of the thiazine ring. Preparation of the O-benzoyl, N-benzoyl, and O,N-dibenzoyl derivatives of 2-(β-hydroxyethyl-mercapto)aniline (VIII) has permitted clarification of the confusion in the literature with respect to the derivatives of Va and VIII. Compound XVIII, the 1,1-dioxide of IIIa, undergoes C-alkylation at the 2-position when treated with alkyl halides, rather than O-alkylation as previously suggested.