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Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, phar-macological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical char-acterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl L-valinate (MMB), methyl L-tert-leucinate (MDMB), methyl L-phenylalaninate (MPP), L-valinamide (AB), L-tert-leucinamide (ADB), L-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB1 binding affinity (Ki= 0.17–39 nM), followed by indole-(Ki= 0.95–160 nM) and then 7-azaindole-derived SCRAs (Ki= 5.4–271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (Ki= 0.17–14 nM) generally showing the greatest affinities, followed by valine derivatives (Ki= 0.72–180 nM), and then phe-nylalanine derivatives (Ki= 2.5–271 nM). Adamantyl head groups (Ki= 8.8–59 nM)