Selective antagonism of N-methyl-d-aspartate (NMDA) 2B subunit containing receptors has been suggested to have potential therapeutic application for multiple CNS disorders. The amino terminal NR2B residues 1 to 282 were found to be both necessary and sufficient for the binding and function of highly NR2B subunit specific antagonists like ifenprodil and CP-101,606. Using a genetic approach in mice, we successfully replaced the murine NR2B gene function by "knocking-in" (KI) a chimeric human NR2A/B cDNA containing the minimal domain abolishing ifenprodil binding into the endogenous NR2B locus. Patch-clamp recording from hippocampal cultures of the NR2B KI mice demonstrated that their NMDA receptors have reduced sensitivity to both ifenprodil and CP-101,606, as predicted, but also have a lower affinity for glycine. The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo.

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.

Novel (E)-N1-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had ∼1000-fold lower IC50 in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.

A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.

Homoquinolinate, a derivative of the endogenous NMDA agonist, quinolinate, has been shown to display higher affinity for Xenopus oocytes expressing NR2A‐ and NR2B‐containing receptors, compared to NR2C‐ and NR2D‐containing receptors, whilst autoradiographical experiments subsequently showed that [3H]homoquinolinate labelled a subpopulation of NMDA receptors in rat brain sections, with a similar distribution to NR2B‐containing receptors. In this study, we have shown that NMDA‐specific [3H]homoquinolinate binding to rat brain membranes comprised 44% of total binding with a Bmax value of 5.73 pmol/mg protein, which was inhibited by NMDA with Ki=0.867 µm. However, NMDA‐specific [3H]homoquinolinate binding was not observed for a number of human recombinant NMDA receptors investigated, suggesting that there are subtle differences between the binding sites of recombinant and native receptors. Electrophysiological experiments revealed that homoquinolinate activated human recombinant NR1a/NR2A, NR1a/NR2B and NR1a/NR2A/NR2B receptors with EC50 values of 25.2, 13.8 and 9.04 µm, respectively, with intrinsic activities of 148, 93.3 and 125%, respectively, compared to glutamate (=100%). In contrast to an autoradiographical study, these radioligand binding and electrophysiological experiments suggest that homoquinolinate is not highly selective for NR2B‐containing receptors.

This article is the third of a series of articles that in-troduces new models and concepts presented in the latest set of Canadian occupational therapy guidelines entitled, Enabling Occupation II: Advancing Occupa-tional Vision for Health, Well-Being and Justice through Occupation (Townsend & Polatajko, 2007).In Enabling Occupation II, the Canadian Model of Client-Centred Enablement (CMCE) is presented. This model is “a visual metaphor for client-centred enable-ment” (see Figure 4.3) (Townsend et al., 2007, p. 109) and depicts the relationship between therapist and client, as well as an array of enablement skills used in therapeutic relationships. Chapter four of Enabling Oc-cupation II describes how the CMCE, “embraces enable-ment as the core competency of occupational therapy” (Townsend et al., p. 109). The chapter is exciting to read because it makes explicit the ideas about enablement that have implicitly guided occupational therapy prac-tice for years. The CMCE displays ‘what’ occupational therapists ‘do’ with their clients who may be individual, families, groups, communities, organizations or popu-lations. Furthermore the CMCE defines a spectrum of enablement skills that include the actions of adapt, ad-vocate, coach, collaborate, consult, coordinate, design/build, educate, engage and specialize as the key skills for client-centred, occupation-based enablement. A fascinating idea portrayed in the CMCE is that enablement may fall on a continuum. While we would wish for all enablement to be effective, there are a “continuum of possibilities from ineffective to effective enablement” (Townsend et al., p. 128). Four decision-making points for the enablement continuum have been established and include; ineffective enablement, missed enablement, minimal enablement and effective enablement (see Figure 4.4). The text encourages us to critically reflect on enablement, recognizing that “com-plex practice conditions as well as therapist choices determine possibilities for enablement” (Townsend et al., p. 130). Last fall, the CMCE and the enablement continuum was discussed with a group of occupational therapists with diverse practice backgrounds. These 15 thera-pists were participants in a distance-education theory course at Dalhousie University’s School of Occupational Therapy. Here are some of the comments they made in their on-line discussion. *****